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No Meaningful Drug Interactions with Doravirine, Lamivudine and Tenofovir Disoproxil Fumarate Coadministration

No Meaningful Drug Interactions with Doravirine, Lamivudine and Tenofovir Disoproxil Fumarate... Antiviral Therapy 2019; 24:443–450 (doi: 10.3851/IMP3324) Original article No meaningful drug interactions with doravirine, lamivudine and tenofovir disoproxil fumarate coadministration 1,2 1 1 1 3 1 Matt S Anderson , Jocelyn Gilmartin , Li Fan , Ka Lai Yee , Walter K Kraft , Ilias Triantafyllou , 1 1 1 1 Christina Reitmann , Ying Guo , Rachael Liu , Marian Iwamoto * Merck & Co., Inc., Kenilworth, NJ, USA Present address: Certara USA, Inc., Princeton, NJ, USA Thomas Jefferson University, Philadelphia, PA, USA *Corresponding author e-mail: marian_iwamoto@merck.com Background: Doravirine (DOR) is a novel non-nucleoside concentration–time curve from time 0 extrapolated reverse transcriptase inhibitor available as a single tablet to infinity (AUC ) and observed plasma concentra- 0–∞ and a three-drug combination with lamivudine (3TC) and tions at 24 h post-dose (C ; DOR+TDF/DOR) were 24 h tenofovir disoproxil fumarate (TDF) to treat HIV-1 infec- 0.95 (0.80,  1.12) and 0.94 (0.78, 1.12), respectively. tion. These analyses assessed pharmacokinetic (PK) inter- Study 2: GMRs (90% CI) of DOR AUC and C 0–∞ 24  h actions with coadministration. (DOR+3TC+TDF/DOR) were 0.96 (0.87, 1.06) and 0.94 Methods: Two trials were conducted. Study 1: two-period, (0.83, 1.06), respectively. GMRs (90% CI) of 3TC and fixed-sequence; eight healthy participants; Period 1, DOR tenofovir AUC (DOR+3TC+TDF/3TC+TDF) were 0.94 0–∞ 100 mg followed by ≥7-day washout; Period 2, TDF 300 mg (0.88,  1.00) and 1.11 (0.97, 1.28), respectively. Study once daily for 18 days, coadministration of DOR 100 mg drugs were generally well tolerated. on day 14. Study 2: three-period, crossover, 15 healthy Conclusions: Multiple doses of TDF did not have a clini- participants; Treatment A, DOR 100 mg; Treatment B, 3TC cally meaningful effect on DOR PK. The PK of DOR were 300 mg + TDF 300 mg; Treatment C, DOR 100 mg + 3TC similar when administered alone or in combination with 300 mg + TDF 300 mg; ≥7-day washout between periods. 3TC and TDF. DOR had no meaningful effect on the PK of Results: Study 1: geometric mean ratios (GMRs; 3TC and tenofovir. 90% confidence interval [CI]) of DOR area under the Introduction HIV continues to be a major global health challenge, from at least two different mechanistic classes, as treat- infecting more than 36.9 million people worldwide [1]. ment with agents across classes has demonstrated sus- In 2017, approximately 1.8 million people became tained virological response [2,3]. Despite the array of infected with HIV, and 0.9 million people died from therapies currently available, no single antiviral agent AIDS-related causes globally [1]. Antiretroviral therapy or combination of agents is appropriate for every per- (ART) has been seminal in reducing the morbidity and son living with HIV, and there are often additional chal- mortality associated with HIV type-1 (HIV-1) infection. lenges in finding the most suitable treatment including There are over 25 agents available for use in seven major issues with resistance, tolerability, unfavourable drug– mechanistic classes of ARTs: nucleoside reverse tran- drug interaction (DDI) profiles, high pill burden and/or scriptase inhibitors (NRTIs), non-nucleoside reverse unfavourable dosing frequency [2,3]. transcriptase inhibitors (NNRTIs), protease inhibitors, NNRTIs were formerly the cornerstone of front-line a fusion inhibitor, a C-C chemokine receptor type 5 therapy; however, as protease inhibitors and integrase antagonist, a CD4-directed post-attachment inhibitor, strand transfer inhibitors offer a greater barrier to resist- and integrase strand transfer inhibitors [2]. Current ance, improved tolerability and more rapid viral sup- guidelines generally recommend three antiviral agents pression for people living with HIV, they are no longer ©2019 International Medical Press 1359-6535 (print) 2040-2058 (online) 443 AVT-19-OA-4508_Anderson.indd 443 AVT-19-OA-4508_Anderson.indd 443 22/11/2019 13:16:36 22/11/2019 13:16:36 MS Anderson et al. primarily recommended in major international guide- Clinical drug-interaction studies with CYP3A and trans- lines [2,3]. Although the NNRTIs efavirenz and rilpi- porter substrates demonstrated no substantive interac- virine remain as alternative treatment options under tions [16–19]. particular clinical circumstances, efavirenz has a rela- As a commonly used NRTI with a well-characterized tively high rate of central nervous system-related adverse PK profile, 3TC is eliminated primarily via urinary excre- events (AEs), limiting its tolerability; and rilpivirine has tion by active organic cationic secretion and is not a lower virological efficacy, particularly in patients with known perpetrator of DDIs [20]. TDF is another com- high baseline HIV-1 RNA (>100,000 copies/ml) and monly used NRTI which, following absorption, is rapidly + 3 low CD4 T-cell counts (<200 cells/mm ) [2]. As such, converted to its active metabolite, tenofovir, and cleared an unmet medical need exists for improved ART, includ- by renal elimination [21,22]. Although tenofovir has ing new NNRTI agents with improved tolerability and been shown to reduce CYP1A substrate concentrations, efficacy compared with currently available drugs in it is not a substrate, inducer or inhibitor of CYP3A [21]. this class. Tenofovir DDIs have been reported with didanosine, Doravirine (DOR, MK-1439) is a novel NNRTI resulting in increased didanosine concentrations after designed to overcome the common resistance mutations coadministration [23] and with ritonavir-boosted and which can reduce the effectiveness of other antiretrovi- unboosted atazanavir, with coadministration result- rals in this class. Preclinical studies have demonstrated ing in decreased atazanavir plasma concentrations and DOR to be active against wild-type HIV-1, as well as the increased tenofovir concentration [21,24]. two most prevalent NNRTI-associated mutant viruses Based on the metabolic profiles of DOR, 3TC and (K103N and Y181C substitutions) [4]. In two Phase TDF, a meaningful PK DDI is unlikely. However, due III studies, DOR demonstrated robust and durable effi- to the use of these three agents in combination, and the cacy, and was generally well tolerated [5,6]. In the first unexpected effects seen with TDF when coadministered of these, DOR coadministered with lamivudine (3TC)/ with other antiretroviral agents, two clinical trials were tenofovir disoproxil fumarate (TDF) was associated conducted to further explore potential DDIs. with fewer treatment-emergent central nervous system AEs compared with the combination of efavirenz and Methods emtricitabine/TDF [6]. In the second study, which com- Study design pared DOR to ritonavir-boosted darunavir when both were coadministered with investigator-selected NRTIs Study 1 (protocol MK-1439-003) was an open-label, (TDF and emtricitabine or abacavir and 3TC), there two-period, fixed-sequence study in eight healthy male were no clinically relevant differences in the incidence participants, conducted between 19 September and of specific AEs, with the exception of a higher incidence 23 November 2011. In Period 1, all participants received of diarrhoea in the darunavir group [5]. In both studies, a single oral dose of DOR 100 mg after an overnight DOR combination therapy was associated with a more fast. After a washout of ≥7 days, Period 2 began; all par- favourable lipid profile and similar antiviral efficacy over ticipants received a daily dose of TDF 300 mg for 18 48 weeks of treatment [5,6]. DOR 100 mg administered days with coadministration of a single dose of DOR 100 once daily is indicated for the treatment of HIV-1 infec- mg on day 14. All doses of TDF alone were administered tion in combination with other ARTs, including 3TC and within 30 min prior to or after a standard meal; on day TDF, and is available for use as a single tablet or in a 14, study drugs were coadministered in the fasted state. fixed dose combination tablet with 3TC and TDF [7,8]. Study 2 (protocol MK-1439-038) was an open-label, DOR is cleared primarily by oxidative metabolism single-dose, randomized, three-period crossover study via cytochrome P450 (CYP)3A [9]. Thus, drugs that in 15 healthy participants, conducted in January 2015. induce or inhibit CYP3A may affect DOR elimination; In the three treatment periods, participants received the this interaction has been confirmed in clinical DDI stud- following in a randomized manner: a single oral dose ies with the antibiotics rifabutin and rifampin, the anti- of DOR 100 mg; coadministration of single oral doses fungal ketoconazole, and the antiretrovirals ritonavir of 3TC 300 mg and TDF 300 mg; and coadministra- and efavirenz [10–14]. DOR was also shown to be a tion of single oral doses of DOR 100 mg, 3TC 300 mg substrate for P-glycoprotein (P-gp) [9]; however, stud- and TDF 300 mg. Study drugs were administered after ies conducted to date revealed that P-gp does not have an overnight fast. The washout period between drug a significant role in DOR absorption or elimination, administrations was ≥7 days. suggesting that the likelihood of P-gp affecting DOR The studies were conducted in accordance with prin- pharmacokinetics (PK) is minimal [9]. In vitro studies ciples of Good Clinical Practice and were approved by demonstrated that DOR is not expected to have a mean- the appropriate institutional review boards (Study  1: ingful impact on the PK of other compounds, including Thomas Jefferson University IRB, Philadelphia, PA, substrates of all major CYPs and drug transporter [15]. USA; Study 2: the Institutional Review Board of 444 ©2019 International Medical Press AVT-19-OA-4508_Anderson.indd 444 AVT-19-OA-4508_Anderson.indd 444 22/11/2019 13:16:36 22/11/2019 13:16:36 Doravirine, lamivudine and tenofovir drug–drug interactions Optimum Clinical Research Inc., Oshawa, ON, Can- maximum plasma concentration (T ) and the apparent max ada) and regulatory agencies. terminal half-life (t ; calculated as the quotient of the 1/2 natural log of 2 [ln (2)] and apparent terminal elimina- Study populations tion rate constant) were calculated using Phoenix Win- Study 1 included healthy men, 18–50 years of age with Nonlin (Version 6.3; Certara, Princeton, NJ, USA). The a body mass index ≤35 kg/m . Study 2 included healthy observed plasma concentrations at 24 h post-dose (C ) 24 h men and women, 18–65 years of age with a body mass were obtained directly from plasma concentrations using index of 19–33 kg/m . In both studies, participants with SAS (Version 9.3; SAS Institute Inc., Cary, NC, USA). In a history of clinically significant medical conditions, Study 2, values of the same PK parameters as in Study 1 estimated creatinine clearance of ≤80 ml/min (based were calculated for DOR, 3TC and tenofovir using the ® ® on Cockcroft–Gault equation), drug or alcohol abuse, non-compartmental approach in Phoenix WinNonlin . recent smoking or positive test for HIV, or who were hepatitis B or C positive, were excluded. Concomitant Safety and tolerability medications were not permitted from 14 days or 5 half- Safety and tolerability were assessed in both studies by lives prior to the start of the trials until trial completion physical examinations, vital signs, laboratory assess- (although participants could receive concomitant ther- ments and AE monitoring. apy and continue in the study if the sponsor and inves- tigator agreed). Participants in both studies provided Statistics written, informed consent prior to any study-related In both studies, the individual values of AUC , C 0–∞ max procedures being performed. and C were ln-transformed prior to analysis and 24 h evaluated separately using a linear mixed-effect model. Sample collection and plasma concentration In Study 1, treatment was a fixed effect and subject determination was a random effect. A two-sided 90% CI for the geo- In Study 1, blood samples for assay of DOR plasma metric mean ratio (GMR; DOR+TDF/DOR alone) was concentration were obtained pre-dose and up to 120 h generated for DOR AUC , C and C from the 0–∞ max 24 h following administration of DOR on day 1 (Period 1), mixed-effect model. Tenofovir PK were not analysed. and coadministration of DOR and TDF on day 14 Descriptive statistics were provided for T and appar- max (Period 2). In Study 2, blood samples were collected pre- ent t . Median values were reported for T while the 1/2 max dose and up to 72 h post-dose. geometric mean was reported for t . 1/2 In both studies, DOR plasma concentrations were In Study 2, AUC , C and C were analysed using 0–∞ max 24 h analysed by liquid–liquid extraction for analyte isola- a linear mixed-effect model appropriate for a three- tion followed by liquid chromatographic–tandem mass period, two-treatment crossover design with fixed- spectrometric (LC-MS/MS) detection using a vali- effect terms for treatment and period. An unstructured dated method (MSD, Oss, the Netherlands) [13]. The covariance matrix was used to allow for unequal treat- lower limit of quantitation was 1 ng/ml. The analytical ment variances and to model the correlation between range of the assay was 1.00–1,000 ng/ml. For Study 1, different treatment measurements within the same sub- the inter-day accuracy of the quality control samples ject via the REPEATED statement SAS PROC MIXED. was 103.3–105.0%, and the inter-day precision was Kenward and Roger’s method was used to calculate the 3.3–5.2%. For Study 2, the inter-day accuracy was denominator degrees of freedom for the fixed effects 97.0–99.5%, and the inter-day precision was 3.5–5.3%. (DDFM=KR). In Study 2, following extraction, the plasma concentra- A two-sided 90% CI for the GMRs (DOR+3TC+ tions of 3TC and tenofovir were determined by vali- TDF/DOR alone) was generated for DOR AUC , 0–∞ dated achiral LC-MS/MS detection methods (Pharma C and C . max 24 h Medica Research, Inc., Mississauga, ON, Canada). The In addition, 95% CIs were generated from the above analytical ranges of the assays were 5.00–3,000 ng/ml mixed-effect model for geometric means by treatment for 3TC and 2.00–500 ng/ml for tenofovir. For 3TC, for DOR AUC , C and C . 3TC and tenofovir 0–∞ max 24 h the inter-day accuracy of the quality control samples AUC , C and C after coadministration of DOR 0–∞ max 24 h was 97.8–105.2%, and the inter-day precision was 100 mg, 3TC 300 mg and TDF 300 mg were analysed 0.9–3.3%. For tenofovir, the inter-day accuracy was in a similar manner. 98.5–101.5% and the inter-day precision was 1.0–2.2%. Results PK evaluations Study populations In Study 1, DOR area under the concentration–time curve from time 0 extrapolated to infinity (AUC ), A total of eight healthy male participants were enrolled 0–∞ maximum plasma concentration (C ), time to reach in Study 1; one participant discontinued on day 11 in max Antiviral Therapy 24.6 445 AVT-19-OA-4508_Anderson.indd 445 AVT-19-OA-4508_Anderson.indd 445 22/11/2019 13:16:36 22/11/2019 13:16:36 MS Anderson et al. Period 2 due to an AE that was not study-drug related. [DOR alone], headache [DOR alone], rash [TDF] and A total of 15 participants were enrolled in Study 2, all somnolence [DOR+TDF]). Headache was the only AE of whom completed the study. Demographics for par- reported by more than one participant. One participant ticipants from both studies are summarized in Table 1. was discontinued on day 11 of Period 2 due to an AE that was not study-drug related. PK evaluations In Study 2, 5 of the 15 participants (33.3%) reported Study 1: mean plasma concentration–time curves for a total of 5 AEs. One incidence of somnolence (DOR DOR alone or coadministered after multiple doses of alone) and one of headache (DOR+3TC+TDF) were TDF are shown in Figure 1A. DOR PK summary statis- considered to be related to study treatment. tics are listed in Table 2. The GMRs (90% CI) of DOR AUC and C (DOR+TDF/DOR alone) were 0.95 Discussion 0–∞ 24 h (0.80, 1.12) and 0.94 (0.78, 1.12), respectively. The GMR (90% CI) of DOR C was 0.80 (0.64, 1.01). There is a continuing need for improved therapeutics max T and apparent t were similar between the two for the treatment of HIV-1 infection. DOR is a novel max 1/2 treatment groups. HIV-1 NNRTI that is indicated for use in combination Study 2: the mean plasma concentration–time pro- with other antiretroviral agents, and as a fixed-dose files for DOR, 3TC and tenofovir following DOR or regimen with 3TC and TDF as a complete regimen, 3TC+TDF administration or DOR+3TC+TDF coad- for the treatment of HIV-1 infection in adults with no ministration are shown in Figure 1B–1D. DOR, 3TC prior antiretroviral treatment history [7,8]. Although and tenofovir PK summary statistics are listed in Tables the metabolic profiles of these agents do not suggest 3 and 4. The GMRs (90% CI) of DOR AUC and C that there would be meaningful DDIs with coadmin- 0–∞ max (DOR+3TC+TDF/DOR alone) were 0.96 (0.87, 1.06) istration, clinical investigation was pursued to further and 0.97 (0.88, 1.07), respectively. The GMRs (90% CI) evaluate potential DDIs. of 3TC AUC and C (DOR+3TC+TDF/3TC+TDF) Data from the two studies reported here demon- 0–∞ max were 0.94 (0.88, 1.00) and 0.92 (0.81, 1.05), respec- strate that neither coadministration of multiple doses tively. GMRs (90% CI) of tenofovir AUC and C of TDF nor coadministration with single doses of 0–∞ max (DOR+3TC+TDF/3TC+TDF) were 1.11 (0.97, 1.28) 3TC+TDF (at the recommended therapeutic dose and 1.17 (0.96, 1.42), respectively. Individual PK ratios of 300 mg each for 3TC and TDF) have a clinically and corresponding GMR plots of DOR, 3TC and teno- meaningful impact on DOR PK. This is evidenced by fovir with and without coadministration of companion a lack of a meaningful effect on DOR AUC , C 0–∞ max agents are shown in Figure 2. and C , with AUC and C GMRs close to unity 24 h 0–∞ 24 h and C reduced by 20% following multiple doses of max Safety TDF. The minor reduction in DOR C is not antici- max All treatment combinations were generally well tolerated. pated to have any meaningful impact on DOR effi- There were no serious AEs, events of clinical interest or cacy or safety, as a DOR Phase IIb trial demonstrated deaths reported during the studies. All AEs were mild in similar efficacy to efavirenz across a range of doses intensity, of limited duration and resolved by the end of from 25 to 200 mg [25]. The single-dose DDI assess- the study. ment in Study 2 further supports a lack of interaction, In Study 1, three of the eight participants (37.5%) with DOR AUC , C and C all without clinically 0–∞ max 24 h reported a total of ten AEs, four of which were con- meaningful changes. sidered to be related to study treatment (fatigue, 3TC and TDF are commonly administered together, without evidence of a meaningful interaction when coad- ministered [20,21]. As such, Study 2 was designed with coadministration of 3TC+TDF without evaluation of Table 1. Study population demographics each of the separate components. Data showed the lack Characteristic Study 1 (n=8) Study 2 (n=15) of a meaningful effect of DOR on either 3TC or tenofo- vir PK. Tenofovir exposure and C increased slightly max Gender (by 11% and 17%, respectively) with coadministration Male, n (%) 8 (100) 7 (46.7) of DOR. These changes are not clinically meaningful, Female, n (%) 0 8 (53.3) based on drug-interaction effects and dosing recommen- Mean age, years (range) 44.3 (36–50) 44 (23–56) dations for TDF [21]. The cause of the effect is unknown. Mean body mass index, kg/m ±sd 29.2 ±2.0 26.2 ±2.9 It has been noted that tenofovir is a substrate of P-gp Race and breast cancer-resistant protein (BCRP) transport- Asian, n (%) 0 2 (13.3) ers [21]. Atazanavir and other HIV protease inhibitors, Black or African American, n (%) 6 (75.0) 3 (20.0) White, n (%) 2 (25.0) 10 (66.7) which are P-gp and BCRP inhibitors, modestly increase 446 ©2019 International Medical Press AVT-19-OA-4508_Anderson.indd 446 AVT-19-OA-4508_Anderson.indd 446 22/11/2019 13:16:36 22/11/2019 13:16:36 Doravirine, lamivudine and tenofovir drug–drug interactions Figure 1. Plasma concentration–time profiles A B 10,000 2,000 3,000 3,000 1,000 1,000 2,500 2,500 500 10 2,000 2,000 1,500 1,500 0 24 48 72 96 120 0 6 18 30 42 54 66 78 Time, h Time, h 1,000 1,000 DOR DOR DOR + 3TC + TDF DOR+TDF 500 0 24 48 72 96 120 0 6 12 18 24 30 36 42 48 54 60 66 72 78 Time, h Time, h C D 4,000 300 1,000 3,000 50 2,000 0 6 18 30 42 54 66 78 0 6 18 30 42 54 66 78 Time, h Time, h 1,000 3TC + TDF 100 3TC + TDF DOR + 3TC + TDF DOR + 3TC + TDF 0 0 0 6 12 18 24 30 36 42 48 54 60 66 72 78 0 6 12 18 24 30 36 42 48 54 60 66 72 78 Time, h Time, h Arithmetic mean (± standard deviation) plasma concentration–time profiles of (A) single-dose doravirine (DOR) 100 mg alone and coadministered with tenofovir disoproxil fumarate (TDF) 300 mg after 14 days of once-daily TDF administration (n=8, inset=semi-log scale); (B) single-dose DOR 100 mg alone and coadministered with single doses of lamivudine (3TC) 300 mg + TDF 300 mg; (C) single-dose 3TC 300 mg following administration of 3TC 300 mg + TDF 300 mg and DOR 100 mg + 3TC 300 mg + TDF 300 mg and (D) tenofovir following administration of 3TC 300 mg + TDF 300 mg and DOR 100 mg + 3TC 300 mg + TDF 300 mg (n=15, inset=log-linear scale for (B), (C) and (D)). tenofovir plasma concentrations, although not to a data demonstrating minimal effect of TDF on DOR PK, clinically meaningful level, likely secondary to P-gp and a single-dose assessment was considered an appropriate BCRP inhibition [21,26,27]. However, in vitro observa- approach for Study 2 and is anticipated to be predictive of tions with DOR have shown that it is not an inhibitor of multiple-dose behaviour [28]. The results of these studies P-gp, indicating that interactions between DOR and P-gp did not demonstrate any substantive effect and indicate are unlikely to be the cause of the increases to plasma that, with multiple-dose administration, there would not tenofovir levels in the current study [15]. be a meaningful PK DDI between these agents. Study 1 was designed to assess the impact of TDF Administration of DOR, 3TC and TDF individually at steady state on DOR PK to maximize any poten- and in combination was generally well tolerated, pro- tial inductive or time-dependent effects of TDF. While viding further evidence of the tolerability of DOR alone Study 2 was conducted with single-dose administration and in combination with 3TC and TDF. The most com- only, no inductive effects by DOR, 3TC or tenofovir mon treatment-related AEs in both Study 1 and Study 2 were anticipated and there is no time dependence for the were headache and somnolence, which have also been PK of DOR, 3TC or tenofovir. Moreover, with Study 1 reported in DOR Phase III studies  [5,6]. The  lack of Antiviral Therapy 24.6 447 AVT-19-OA-4508_Anderson.indd 447 AVT-19-OA-4508_Anderson.indd 447 22/11/2019 13:16:37 22/11/2019 13:16:37 3TC plasma concentration, ng/ml DOR plasma concentration, nM DOR plasma 3TC plasma concentration, nM concentration, ng/ml DOR plasma concentration, nM Tenofovir plasma concentration, ng/ml DOR plasma Tenofovir plasma concentration, nM concentration, ng/ml MS Anderson et al. Table 2. Plasma PK of DOR 100 mg administered alone or with multiple-dose TDF 300 mg administered once daily for 14 days to healthy participants DOR+TDF DOR DOR+TDF/DOR PK parameter n GM 95% CI n GM 95% CI GMR 90% CI rMSE AUC , h•mM 7 33.4 25.9, 43.2 8 35.3 27.5, 45.3 0.95 0.80, 1.12 0.162 0–∞ C , nM 7 547 430, 697 8 584 463, 738 0.94 0.78, 1.12 0.171 24 h C , nM 7 1,310 965, 1,780 8 1,630 1,210, 2,190 0.80 0.64, 1.01 0.216 max T , h 7 3.0 1.0, 7.9 8 2.5 0.5, 5.0 max t , h 7 15.4 25.0 8 14.4 24.7 Root mean square error (rMSE; residual error) from the linear mixed-effect model. When multiplied by 100 approximates the within-subject % coefficient of variation b c (CV) on the raw scale. Back-transformed least-squares mean (LSM) and CI from linear mixed-effects model performed on natural log-transformed values. Median (minimum, maximum) reported for time to reach maximum plasma concentration (T ). Geometric mean (GM) and % geometric CV reported for apparent elimination max half-life (t ). AUC , area under the concentration–time curve from time 0 to infinity; C , maximum plasma concentration; C , concentration of analyte in plasma 1/2 0–∞ max 24 h 24 h after administration; DOR, doravirine; GMR, geometric mean ratio; PK, pharmacokinetic; TDF, tenofovir disoproxil fumarate. Table 3. Plasma PK of DOR 100 mg administered alone or with single-dose TDF 300 mg and 3TC 300 mg to healthy participants DOR+3TC+TDF DOR DOR+3TC+TDF/DOR PK parameter n GM 95% CI n GM 95% CI GMR 90% CI Intra-subject %CV AUC , h•mM 15 37.7 28.7, 49.4 15 39.1 31.5, 48.6 0.96 0.87, 1.06 15.2 0–∞ C , nM 15 507 332, 774 15 541 390, 750 0.94 0.83, 1.06 19.6 24 h C , nM 15 2,030 1,720, 2,400 15 2,090 1,810, 2,420 0.97 0.88, 1.07 15.1 max T , h 15 2.0 1.0, 6.0 15 3.0 1.0, 4.0 max t , h 15 13.5 40.6 15 13.8 31.9 a 2 2 b Estimated based on the elements of the variance-covariance matrix as: coefficient of variation (CV; %) = 100*sqrt[(sA + sB - 2*sAB)/2]. Back-transformed least-squares mean (LSM) and CI from linear mixed-effects model performed on natural log-transformed values. Median (minimum, maximum) reported for time to reach maximum plasma concentration (T ). Geometric mean (GM) and % geometric CV reported for apparent elimination half-life (t ). AUC , area under max 1/2 0–∞ the concentration–time curve from time 0 to infinity; C , maximum plasma concentration; C , concentration of analyte in plasma 24 h after administration; max 24 h DOR, doravirine; GMR, geometric mean ratio; PK, pharmacokinetic; TDF, tenofovir disoproxil fumarate; 3TC, lamivudine. Table 4. Plasma PK of 3TC and tenofovir following single-dose administration of 3TC 300 mg + TDF 300 mg or DOR 100 mg + 3TC 300 mg + TDF 300 mg to healthy participants DOR+3TC+TDF 3TC+TDF DOR+3TC+TDF/3TC+TDF PK parameter n GM 95% CI n GM 95% CI GMR 90% CI for GMR Intra-subject %CV 3TC AUC , h•ng/ml 15 14,200 12,400, 16,200 15 15,000 13,800, 16,500 0.94 0.88, 1.00 9.7 0–∞ C , ng/ml 15 2,910 2,460, 3,450 15 3,150 2,760, 3,600 0.92 0.81, 1.05 19.4 max T , h 15 1.00 1.0, 2.0 15 1.00 0.5, 2.0 max t , h 15 15.9 57.6 15 15.7 32.2 Tenofovir AUC , h•ng/ml 15 2,790 2,470, 3,150 15 2,500 2,090, 2,990 1.11 0.97, 1.28 20.5 0–∞ C , ng/ml 15 338 286, 400 15 289 237, 352 1.17 0.96, 1.42 29.7 max T , h 15 1.0 0.5, 2.0 15 1.00 0.5, 1.0 max t , h 15 20.9 18.5 15 19.7 12.6 a 2 2 b Estimated based on the elements of the variance-covariance matrix as: coefficient of variation (CV; %) = 100*sqrt[(sA + sB - 2*sAB)/2]. Back-transformed least-squares mean (LSM) and CI from linear mixed-effects model performed on natural log-transformed values. Median (minimum, maximum) reported for time to reach maximum plasma concentration (T ). Geometric mean (GM) and % geometric CV reported for apparent elimination half-life (t ). AUC , area under the max 1/2 0–∞ concentration–time curve from time 0 to infinity; C , maximum plasma concentration; DOR, doravirine; GMR, geometric mean ratio; PK, pharmacokinetic; TDF, max tenofovir disoproxil fumarate; 3TC, lamivudine. DDIs between DOR and 3TC+TDF supports the fixed- used in a recently reported Phase III study (discussed in dose, three-drug, single-tablet regimen (MK-1439A the Introduction) [6]. [DOR 100 mg/3TC 300  mg/TDF  300  mg]) that has In summary, multiple doses of TDF coadministered been developed [29], and which was the formulation with a single dose of DOR did not have a clinically 448 ©2019 International Medical Press AVT-19-OA-4508_Anderson.indd 448 AVT-19-OA-4508_Anderson.indd 448 22/11/2019 13:16:37 22/11/2019 13:16:37 Doravirine, lamivudine and tenofovir drug–drug interactions Figure 2. Individual plasma pharmacokinetic ratios A B 1.4 2.0 1.3 1.2 1.1 1.0 0.9 1.0 0.8 0.7 0.6 0.5 0.5 AUC C C AUC C C 0–∞ 24 h max 0–∞ 24 h max C D 3.5 1.4 3.0 1.2 2.5 2.0 1.0 1.5 0.8 1.0 0.6 AUC C AUC C 0–∞ max 0–∞ max Individual ratios GMR with 90% CI Individual plasma pharmacokinetic ratios and corresponding geometric mean ratios with 90% CIs for (A) single-dose doravirine (DOR) 100 mg with and without multiple-dose tenofovir disoproxil fumarate (TDF) 300 mg (n=8), (B) single-dose DOR 100 mg with and without single-dose lamivudine (3TC) 300 mg + TDF 300 mg (n=15), (C) 3TC after administration of single-dose 3TC 300 mg + TDF 300 mg, with DOR 100 mg versus without DOR (n=15) and (D) tenofovir after administration of 3TC 300 mg + TDF 300 mg, with DOR 100 mg versus without DOR (n=15). AUC , area under the concentration–time curve from time 0 to infinity; C , maximum 0–∞ max concentration; C , concentration of analyte in plasma 24 h after administration. 24 h meaningful effect on the PK of DOR. DOR, 3TC and assistance was funded by Merck Sharp & Dohme Corp., tenofovir PK were similar when administered alone or a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. coadministered. Consequently, coadministration of the three drugs without dose adjustment is supported. Disclosure statement This research was funded by Merck Sharp & Dohme Acknowledgements Corp., a subsidiary of Merck & Co., Inc., Kenilworth, The authors would like to thank the trial staff and NJ, USA. JG, LF, KLY, IT and MI are employees of participants. In addition, the authors would like to thank Merck Sharp & Dohme Corp., a subsidiary of Merck Paul Fackler and Marty Behm (both formerly Merck & & Co., Inc., Kenilworth, NJ, USA, and may own stock Co., Inc., Kenilworth, NJ, USA) for their help with the and/or hold stock options in Merck & Co., Inc., Kenil- study. Medical writing and editorial assistance, under the worth, NJ, USA. MSA, CR, YG and RL were employ- direction of the authors, was provided by Annette Smith ees of Merck Sharp & Dohme Corp., a subsidiary of of CMC AFFINITY, a division of McCann Health Medi- Merck & Co., Inc., Kenilworth, NJ, USA at the time the cal Communications Ltd., Macclesfield, UK, in accordance study was conducted. WKK has no conflicts of interest with Good Publication Practice (GPP3) guidelines. This to disclose. Antiviral Therapy 24.6 449 AVT-19-OA-4508_Anderson.indd 449 AVT-19-OA-4508_Anderson.indd 449 22/11/2019 13:16:37 22/11/2019 13:16:37 DOR+3TC+TDF/3TC+TDF DOR+TDF/DOR DOR+3TC+TDF/3TC+TDF DOR+3TC+TDF/DOR MS Anderson et al. 14. Yee KL, Sanchez RI, Auger P, et al. Evaluation of doravirine Additional file pharmacokinetics when switching from efavirenz to doravirine in healthy subjects. Antimicrob Agents Chemother 2017; 61:e01757-6. Additional file 1: Redacted protocol can be found at 15. Bleasby K, Fillgrove KL, Houle R, et al. In vitro evaluation https://www.intmedpress.com/uploads/documents/4508_ of the drug interaction potential of doravirine. Antimicrob Agents Chemother 2019; 63:e02492-8. Anderson_Addfile1.pdf 16. Anderson MS, Gilmartin J, Cilissen C, et al. Safety, tolerability and pharmacokinetics of doravirine, a novel References HIV non-nucleoside reverse transcriptase inhibitor, after single and multiple doses in healthy subjects. Antivir Ther 1. UNAIDS. Global HIV & AIDS Statistics - 2018 Fact Sheet. 2015; 20:397–405. 2018. (Accessed 14 May 2019.) Available from http://www. 17. Anderson MS, Kaufman D, Castronuovo P, et al. Effect of unaids.org/en/resources/fact-sheet doravirine (MK-1439) on the pharmacokinetics of an oral 2. Panel on Antiretroviral Guidelines for Adults and contraceptive (ethinyl estradiol [EE] and levonorgestrel Adolescents. Guidelines for the Use of Antiretroviral Agents [LNG]). International Workshop on HIV & Women in Adults and Adolescents Living with HIV. 2018. (Accessed (IWHIVW). 20–21 February, 2016, Boston, MA, USA. 14 May 2019.) Available from https://aidsinfo.nih.gov/ Abstract 19. contentfiles/lvguidelines/adultandadolescentgl.pdf 18. Anderson MS, Khalilieh S, Yee KL, et al. A two-way steady- 3. European AIDS Clinical Society. European guidelines for state pharmacokinetic interaction study of doravirine treatment of HIV-positive adults in Europe, version 9.1. (MK-1439) and dolutegravir. Clin Pharmacokinet 2017; 2018. (Accessed 14 May 2019.) Available from http://www. 56:661–669. eacsociety.org/files/2018_guidelines-9.1-english.pdf 19. Khalilieh S, Yee KL, Sanchez RI, et al. Results of a 4. Lai MT, Feng M, Falgueyret JP, et al. In vitro doravirine-atorvastatin drug-drug interaction study. characterization of MK-1439, a novel HIV-1 nonnucleoside Antimicrob Agents Chemother 2017; 61:e01364-16. reverse transcriptase inhibitor. Antimicrob Agents 20. GlaxoSmithKline/ViiV Healthcare. Epivir (lamivudine) Chemother 2014; 58:1652–1663. Prescribing Information. 2018. (Accessed 8 March 2019.) 5. Molina JM, Squires K, Sax PE, et al. Doravirine versus Available from https://www.gsksource.com/pharma/content/ ritonavir-boosted darunavir in antiretroviral-naive adults dam/GlaxoSmithKline/US/en/Prescribing_Information/ with HIV-1 (DRIVE-FORWARD): 48-week results of a Epivir/pdf/EPIVIR-PI-PIL.PDF randomised, double-blind, Phase 3, non-inferiority trial. 21. Gilead Sciences Inc. Viread (tenofovir disproxil fumarate) Lancet HIV 2018; 5:e211–e220. prescribing information. 2018. (Accessed 8 March 2019.) 6. Orkin C, Squires KE, Molina JM, et al. Doravirine/ Available from http://www.gilead.com/~/media/Files/pdfs/ lamivudine/tenofovir disoproxil fumarate is non-inferior medicines/liver-disease/viread/viread_pi.pdf to efavirenz/emtricitabine/tenofovir disoproxil fumarate 22. Kearney BP, Flaherty JF, Shah J. Tenofovir disoproxil in treatment-naive adults with human immunodeficiency fumarate: clinical pharmacology and pharmacokinetics. virus-1 Infection: week 48 results of the DRIVE-AHEAD Clin Pharmacokinet 2004; 43:595–612. Trial. Clin Infect Dis 2019; 68:535–544. 23. Kearney BP, Sayre JR, Flaherty JF, Chen SS, Kaul S, 7. Pifeltro (doravirine) prescribing information. Merck Sharp Cheng AK. Drug-drug and drug-food interactions between & Dohme Corp., Whitehouse Station, NJ, USA. 2019. tenofovir disoproxil fumarate and didanosine. J Clin (Accessed 7 October 2019.) Available from https://www. Pharmacol 2005; 45:1360–1367. merck.com/product/usa/pi_circulars/p/pifeltro/pifeltro_ pi.pdf 24. Taburet AM, Piketty C, Chazallon C, et al. Interactions between atazanavir-ritonavir and tenofovir in heavily 8. Delstrigo (doravirine, lamivudine, and tenofovir disoproxil pretreated human immunodeficiency virus-infected patients. fumarate) prescribing information. Merck Sharp & Dohme Antimicrob Agents Chemother 2004; 48:2091–2096. Corp., Whitehouse Station, NJ, USA. 2019. (Accessed 7 October 2019.) Available from https://www.merck.com/ 25. Gatell JM, Morales-Ramirez JO, Hagins DP, et al. Forty- product/usa/pi_circulars/d/delstrigo/delstrigo_pi.pdf eight-week efficacy and safety and early CNS tolerability of doravirine (MK-1439), a novel NNRTI, with TDF/FTC 9. Sanchez RI, Fillgrove KL, Yee KL, et al. Characterisation in ART-naive HIV-positive patients. J Int AIDS Soc 2014; of the absorption, distribution, metabolism, excretion 17:19532. and mass balance of doravirine, a non-nucleoside reverse transcriptase inhibitor in humans. Xenobiotica 2019; 26. Gupta A, Zhang Y, Unadkat JD, Mao Q. HIV protease 49:422–432. inhibitors are inhibitors but not substrates of the human breast cancer resistance protein (BCRP/ABCG2). 10. Khalilieh SG, Yee KL, Sanchez RI, et al. Multiple doses of J Pharmacol Exp Ther 2004; 310:334–341. rifabutin reduce exposure of doravirine in healthy subjects. J Clin Pharmacol 2018; 58:1044–1052. 27. Storch CH, Theile D, Lindenmaier H, Haefeli WE, Weiss J. Comparison of the inhibitory activity of anti- 11. Anderson MS, Chung C, Tetteh E, et al. Effect of ketoconazole HIV drugs on P-glycoprotein. Biochem Pharmacol 2007; on the pharmacokinetics of doravirine (MK-1439), a 73:1573–1581. novel non-nucleoside reverse transcriptase inhibitor for the treatment of HIV-1 infection. 16th International Workshop on 28. FDA. Clinical drug interaction studies — study design, Clinical Pharmacology of HIV & Hepatitis Therapy. 26–28 data analysis, and clinical implications. Guidance for May 2015, Washington, DC, USA. Abstract 58. industry. 2017. (Accessed 10 July 2018.) Available from https://www.fda.gov/downloads/drugs/guidances/ 12. Khalilieh S, Anderson M, Laethem T, et al. Multiple- ucm292362.pdf dose treatment with ritonavir increases the exposure of doravirine. Conference on Retroviruses and Opportunistic 29. Behm MO, Yee KL, Liu R, Levine V, Panebianco D, Infections (CROI). 13–16 February, 2017, Seattle, WA, Fackler P. The effect of food on doravirine bioavailability: USA. Abstract 412. results from two pharmacokinetic studies in healthy subjects. Clin Drug Investig 2017; 37:571–579. 13. Yee KL, Khalilieh SG, Sanchez RI, et al. The effect of single and multiple doses of rifampin on the pharmacokinetics of doravirine in healthy subjects. Clin Drug Investig 2017; 37:659–667. Accepted 2 June 2019; published online 21 August 2019 450 ©2019 International Medical Press AVT-19-OA-4508_Anderson.indd 450 AVT-19-OA-4508_Anderson.indd 450 22/11/2019 13:16:37 22/11/2019 13:16:37 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Antiviral Therapy SAGE

No Meaningful Drug Interactions with Doravirine, Lamivudine and Tenofovir Disoproxil Fumarate Coadministration

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SAGE
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1359-6535
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2040-2058
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10.3851/imp3324
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Antiviral Therapy 2019; 24:443–450 (doi: 10.3851/IMP3324) Original article No meaningful drug interactions with doravirine, lamivudine and tenofovir disoproxil fumarate coadministration 1,2 1 1 1 3 1 Matt S Anderson , Jocelyn Gilmartin , Li Fan , Ka Lai Yee , Walter K Kraft , Ilias Triantafyllou , 1 1 1 1 Christina Reitmann , Ying Guo , Rachael Liu , Marian Iwamoto * Merck & Co., Inc., Kenilworth, NJ, USA Present address: Certara USA, Inc., Princeton, NJ, USA Thomas Jefferson University, Philadelphia, PA, USA *Corresponding author e-mail: marian_iwamoto@merck.com Background: Doravirine (DOR) is a novel non-nucleoside concentration–time curve from time 0 extrapolated reverse transcriptase inhibitor available as a single tablet to infinity (AUC ) and observed plasma concentra- 0–∞ and a three-drug combination with lamivudine (3TC) and tions at 24 h post-dose (C ; DOR+TDF/DOR) were 24 h tenofovir disoproxil fumarate (TDF) to treat HIV-1 infec- 0.95 (0.80,  1.12) and 0.94 (0.78, 1.12), respectively. tion. These analyses assessed pharmacokinetic (PK) inter- Study 2: GMRs (90% CI) of DOR AUC and C 0–∞ 24  h actions with coadministration. (DOR+3TC+TDF/DOR) were 0.96 (0.87, 1.06) and 0.94 Methods: Two trials were conducted. Study 1: two-period, (0.83, 1.06), respectively. GMRs (90% CI) of 3TC and fixed-sequence; eight healthy participants; Period 1, DOR tenofovir AUC (DOR+3TC+TDF/3TC+TDF) were 0.94 0–∞ 100 mg followed by ≥7-day washout; Period 2, TDF 300 mg (0.88,  1.00) and 1.11 (0.97, 1.28), respectively. Study once daily for 18 days, coadministration of DOR 100 mg drugs were generally well tolerated. on day 14. Study 2: three-period, crossover, 15 healthy Conclusions: Multiple doses of TDF did not have a clini- participants; Treatment A, DOR 100 mg; Treatment B, 3TC cally meaningful effect on DOR PK. The PK of DOR were 300 mg + TDF 300 mg; Treatment C, DOR 100 mg + 3TC similar when administered alone or in combination with 300 mg + TDF 300 mg; ≥7-day washout between periods. 3TC and TDF. DOR had no meaningful effect on the PK of Results: Study 1: geometric mean ratios (GMRs; 3TC and tenofovir. 90% confidence interval [CI]) of DOR area under the Introduction HIV continues to be a major global health challenge, from at least two different mechanistic classes, as treat- infecting more than 36.9 million people worldwide [1]. ment with agents across classes has demonstrated sus- In 2017, approximately 1.8 million people became tained virological response [2,3]. Despite the array of infected with HIV, and 0.9 million people died from therapies currently available, no single antiviral agent AIDS-related causes globally [1]. Antiretroviral therapy or combination of agents is appropriate for every per- (ART) has been seminal in reducing the morbidity and son living with HIV, and there are often additional chal- mortality associated with HIV type-1 (HIV-1) infection. lenges in finding the most suitable treatment including There are over 25 agents available for use in seven major issues with resistance, tolerability, unfavourable drug– mechanistic classes of ARTs: nucleoside reverse tran- drug interaction (DDI) profiles, high pill burden and/or scriptase inhibitors (NRTIs), non-nucleoside reverse unfavourable dosing frequency [2,3]. transcriptase inhibitors (NNRTIs), protease inhibitors, NNRTIs were formerly the cornerstone of front-line a fusion inhibitor, a C-C chemokine receptor type 5 therapy; however, as protease inhibitors and integrase antagonist, a CD4-directed post-attachment inhibitor, strand transfer inhibitors offer a greater barrier to resist- and integrase strand transfer inhibitors [2]. Current ance, improved tolerability and more rapid viral sup- guidelines generally recommend three antiviral agents pression for people living with HIV, they are no longer ©2019 International Medical Press 1359-6535 (print) 2040-2058 (online) 443 AVT-19-OA-4508_Anderson.indd 443 AVT-19-OA-4508_Anderson.indd 443 22/11/2019 13:16:36 22/11/2019 13:16:36 MS Anderson et al. primarily recommended in major international guide- Clinical drug-interaction studies with CYP3A and trans- lines [2,3]. Although the NNRTIs efavirenz and rilpi- porter substrates demonstrated no substantive interac- virine remain as alternative treatment options under tions [16–19]. particular clinical circumstances, efavirenz has a rela- As a commonly used NRTI with a well-characterized tively high rate of central nervous system-related adverse PK profile, 3TC is eliminated primarily via urinary excre- events (AEs), limiting its tolerability; and rilpivirine has tion by active organic cationic secretion and is not a lower virological efficacy, particularly in patients with known perpetrator of DDIs [20]. TDF is another com- high baseline HIV-1 RNA (>100,000 copies/ml) and monly used NRTI which, following absorption, is rapidly + 3 low CD4 T-cell counts (<200 cells/mm ) [2]. As such, converted to its active metabolite, tenofovir, and cleared an unmet medical need exists for improved ART, includ- by renal elimination [21,22]. Although tenofovir has ing new NNRTI agents with improved tolerability and been shown to reduce CYP1A substrate concentrations, efficacy compared with currently available drugs in it is not a substrate, inducer or inhibitor of CYP3A [21]. this class. Tenofovir DDIs have been reported with didanosine, Doravirine (DOR, MK-1439) is a novel NNRTI resulting in increased didanosine concentrations after designed to overcome the common resistance mutations coadministration [23] and with ritonavir-boosted and which can reduce the effectiveness of other antiretrovi- unboosted atazanavir, with coadministration result- rals in this class. Preclinical studies have demonstrated ing in decreased atazanavir plasma concentrations and DOR to be active against wild-type HIV-1, as well as the increased tenofovir concentration [21,24]. two most prevalent NNRTI-associated mutant viruses Based on the metabolic profiles of DOR, 3TC and (K103N and Y181C substitutions) [4]. In two Phase TDF, a meaningful PK DDI is unlikely. However, due III studies, DOR demonstrated robust and durable effi- to the use of these three agents in combination, and the cacy, and was generally well tolerated [5,6]. In the first unexpected effects seen with TDF when coadministered of these, DOR coadministered with lamivudine (3TC)/ with other antiretroviral agents, two clinical trials were tenofovir disoproxil fumarate (TDF) was associated conducted to further explore potential DDIs. with fewer treatment-emergent central nervous system AEs compared with the combination of efavirenz and Methods emtricitabine/TDF [6]. In the second study, which com- Study design pared DOR to ritonavir-boosted darunavir when both were coadministered with investigator-selected NRTIs Study 1 (protocol MK-1439-003) was an open-label, (TDF and emtricitabine or abacavir and 3TC), there two-period, fixed-sequence study in eight healthy male were no clinically relevant differences in the incidence participants, conducted between 19 September and of specific AEs, with the exception of a higher incidence 23 November 2011. In Period 1, all participants received of diarrhoea in the darunavir group [5]. In both studies, a single oral dose of DOR 100 mg after an overnight DOR combination therapy was associated with a more fast. After a washout of ≥7 days, Period 2 began; all par- favourable lipid profile and similar antiviral efficacy over ticipants received a daily dose of TDF 300 mg for 18 48 weeks of treatment [5,6]. DOR 100 mg administered days with coadministration of a single dose of DOR 100 once daily is indicated for the treatment of HIV-1 infec- mg on day 14. All doses of TDF alone were administered tion in combination with other ARTs, including 3TC and within 30 min prior to or after a standard meal; on day TDF, and is available for use as a single tablet or in a 14, study drugs were coadministered in the fasted state. fixed dose combination tablet with 3TC and TDF [7,8]. Study 2 (protocol MK-1439-038) was an open-label, DOR is cleared primarily by oxidative metabolism single-dose, randomized, three-period crossover study via cytochrome P450 (CYP)3A [9]. Thus, drugs that in 15 healthy participants, conducted in January 2015. induce or inhibit CYP3A may affect DOR elimination; In the three treatment periods, participants received the this interaction has been confirmed in clinical DDI stud- following in a randomized manner: a single oral dose ies with the antibiotics rifabutin and rifampin, the anti- of DOR 100 mg; coadministration of single oral doses fungal ketoconazole, and the antiretrovirals ritonavir of 3TC 300 mg and TDF 300 mg; and coadministra- and efavirenz [10–14]. DOR was also shown to be a tion of single oral doses of DOR 100 mg, 3TC 300 mg substrate for P-glycoprotein (P-gp) [9]; however, stud- and TDF 300 mg. Study drugs were administered after ies conducted to date revealed that P-gp does not have an overnight fast. The washout period between drug a significant role in DOR absorption or elimination, administrations was ≥7 days. suggesting that the likelihood of P-gp affecting DOR The studies were conducted in accordance with prin- pharmacokinetics (PK) is minimal [9]. In vitro studies ciples of Good Clinical Practice and were approved by demonstrated that DOR is not expected to have a mean- the appropriate institutional review boards (Study  1: ingful impact on the PK of other compounds, including Thomas Jefferson University IRB, Philadelphia, PA, substrates of all major CYPs and drug transporter [15]. USA; Study 2: the Institutional Review Board of 444 ©2019 International Medical Press AVT-19-OA-4508_Anderson.indd 444 AVT-19-OA-4508_Anderson.indd 444 22/11/2019 13:16:36 22/11/2019 13:16:36 Doravirine, lamivudine and tenofovir drug–drug interactions Optimum Clinical Research Inc., Oshawa, ON, Can- maximum plasma concentration (T ) and the apparent max ada) and regulatory agencies. terminal half-life (t ; calculated as the quotient of the 1/2 natural log of 2 [ln (2)] and apparent terminal elimina- Study populations tion rate constant) were calculated using Phoenix Win- Study 1 included healthy men, 18–50 years of age with Nonlin (Version 6.3; Certara, Princeton, NJ, USA). The a body mass index ≤35 kg/m . Study 2 included healthy observed plasma concentrations at 24 h post-dose (C ) 24 h men and women, 18–65 years of age with a body mass were obtained directly from plasma concentrations using index of 19–33 kg/m . In both studies, participants with SAS (Version 9.3; SAS Institute Inc., Cary, NC, USA). In a history of clinically significant medical conditions, Study 2, values of the same PK parameters as in Study 1 estimated creatinine clearance of ≤80 ml/min (based were calculated for DOR, 3TC and tenofovir using the ® ® on Cockcroft–Gault equation), drug or alcohol abuse, non-compartmental approach in Phoenix WinNonlin . recent smoking or positive test for HIV, or who were hepatitis B or C positive, were excluded. Concomitant Safety and tolerability medications were not permitted from 14 days or 5 half- Safety and tolerability were assessed in both studies by lives prior to the start of the trials until trial completion physical examinations, vital signs, laboratory assess- (although participants could receive concomitant ther- ments and AE monitoring. apy and continue in the study if the sponsor and inves- tigator agreed). Participants in both studies provided Statistics written, informed consent prior to any study-related In both studies, the individual values of AUC , C 0–∞ max procedures being performed. and C were ln-transformed prior to analysis and 24 h evaluated separately using a linear mixed-effect model. Sample collection and plasma concentration In Study 1, treatment was a fixed effect and subject determination was a random effect. A two-sided 90% CI for the geo- In Study 1, blood samples for assay of DOR plasma metric mean ratio (GMR; DOR+TDF/DOR alone) was concentration were obtained pre-dose and up to 120 h generated for DOR AUC , C and C from the 0–∞ max 24 h following administration of DOR on day 1 (Period 1), mixed-effect model. Tenofovir PK were not analysed. and coadministration of DOR and TDF on day 14 Descriptive statistics were provided for T and appar- max (Period 2). In Study 2, blood samples were collected pre- ent t . Median values were reported for T while the 1/2 max dose and up to 72 h post-dose. geometric mean was reported for t . 1/2 In both studies, DOR plasma concentrations were In Study 2, AUC , C and C were analysed using 0–∞ max 24 h analysed by liquid–liquid extraction for analyte isola- a linear mixed-effect model appropriate for a three- tion followed by liquid chromatographic–tandem mass period, two-treatment crossover design with fixed- spectrometric (LC-MS/MS) detection using a vali- effect terms for treatment and period. An unstructured dated method (MSD, Oss, the Netherlands) [13]. The covariance matrix was used to allow for unequal treat- lower limit of quantitation was 1 ng/ml. The analytical ment variances and to model the correlation between range of the assay was 1.00–1,000 ng/ml. For Study 1, different treatment measurements within the same sub- the inter-day accuracy of the quality control samples ject via the REPEATED statement SAS PROC MIXED. was 103.3–105.0%, and the inter-day precision was Kenward and Roger’s method was used to calculate the 3.3–5.2%. For Study 2, the inter-day accuracy was denominator degrees of freedom for the fixed effects 97.0–99.5%, and the inter-day precision was 3.5–5.3%. (DDFM=KR). In Study 2, following extraction, the plasma concentra- A two-sided 90% CI for the GMRs (DOR+3TC+ tions of 3TC and tenofovir were determined by vali- TDF/DOR alone) was generated for DOR AUC , 0–∞ dated achiral LC-MS/MS detection methods (Pharma C and C . max 24 h Medica Research, Inc., Mississauga, ON, Canada). The In addition, 95% CIs were generated from the above analytical ranges of the assays were 5.00–3,000 ng/ml mixed-effect model for geometric means by treatment for 3TC and 2.00–500 ng/ml for tenofovir. For 3TC, for DOR AUC , C and C . 3TC and tenofovir 0–∞ max 24 h the inter-day accuracy of the quality control samples AUC , C and C after coadministration of DOR 0–∞ max 24 h was 97.8–105.2%, and the inter-day precision was 100 mg, 3TC 300 mg and TDF 300 mg were analysed 0.9–3.3%. For tenofovir, the inter-day accuracy was in a similar manner. 98.5–101.5% and the inter-day precision was 1.0–2.2%. Results PK evaluations Study populations In Study 1, DOR area under the concentration–time curve from time 0 extrapolated to infinity (AUC ), A total of eight healthy male participants were enrolled 0–∞ maximum plasma concentration (C ), time to reach in Study 1; one participant discontinued on day 11 in max Antiviral Therapy 24.6 445 AVT-19-OA-4508_Anderson.indd 445 AVT-19-OA-4508_Anderson.indd 445 22/11/2019 13:16:36 22/11/2019 13:16:36 MS Anderson et al. Period 2 due to an AE that was not study-drug related. [DOR alone], headache [DOR alone], rash [TDF] and A total of 15 participants were enrolled in Study 2, all somnolence [DOR+TDF]). Headache was the only AE of whom completed the study. Demographics for par- reported by more than one participant. One participant ticipants from both studies are summarized in Table 1. was discontinued on day 11 of Period 2 due to an AE that was not study-drug related. PK evaluations In Study 2, 5 of the 15 participants (33.3%) reported Study 1: mean plasma concentration–time curves for a total of 5 AEs. One incidence of somnolence (DOR DOR alone or coadministered after multiple doses of alone) and one of headache (DOR+3TC+TDF) were TDF are shown in Figure 1A. DOR PK summary statis- considered to be related to study treatment. tics are listed in Table 2. The GMRs (90% CI) of DOR AUC and C (DOR+TDF/DOR alone) were 0.95 Discussion 0–∞ 24 h (0.80, 1.12) and 0.94 (0.78, 1.12), respectively. The GMR (90% CI) of DOR C was 0.80 (0.64, 1.01). There is a continuing need for improved therapeutics max T and apparent t were similar between the two for the treatment of HIV-1 infection. DOR is a novel max 1/2 treatment groups. HIV-1 NNRTI that is indicated for use in combination Study 2: the mean plasma concentration–time pro- with other antiretroviral agents, and as a fixed-dose files for DOR, 3TC and tenofovir following DOR or regimen with 3TC and TDF as a complete regimen, 3TC+TDF administration or DOR+3TC+TDF coad- for the treatment of HIV-1 infection in adults with no ministration are shown in Figure 1B–1D. DOR, 3TC prior antiretroviral treatment history [7,8]. Although and tenofovir PK summary statistics are listed in Tables the metabolic profiles of these agents do not suggest 3 and 4. The GMRs (90% CI) of DOR AUC and C that there would be meaningful DDIs with coadmin- 0–∞ max (DOR+3TC+TDF/DOR alone) were 0.96 (0.87, 1.06) istration, clinical investigation was pursued to further and 0.97 (0.88, 1.07), respectively. The GMRs (90% CI) evaluate potential DDIs. of 3TC AUC and C (DOR+3TC+TDF/3TC+TDF) Data from the two studies reported here demon- 0–∞ max were 0.94 (0.88, 1.00) and 0.92 (0.81, 1.05), respec- strate that neither coadministration of multiple doses tively. GMRs (90% CI) of tenofovir AUC and C of TDF nor coadministration with single doses of 0–∞ max (DOR+3TC+TDF/3TC+TDF) were 1.11 (0.97, 1.28) 3TC+TDF (at the recommended therapeutic dose and 1.17 (0.96, 1.42), respectively. Individual PK ratios of 300 mg each for 3TC and TDF) have a clinically and corresponding GMR plots of DOR, 3TC and teno- meaningful impact on DOR PK. This is evidenced by fovir with and without coadministration of companion a lack of a meaningful effect on DOR AUC , C 0–∞ max agents are shown in Figure 2. and C , with AUC and C GMRs close to unity 24 h 0–∞ 24 h and C reduced by 20% following multiple doses of max Safety TDF. The minor reduction in DOR C is not antici- max All treatment combinations were generally well tolerated. pated to have any meaningful impact on DOR effi- There were no serious AEs, events of clinical interest or cacy or safety, as a DOR Phase IIb trial demonstrated deaths reported during the studies. All AEs were mild in similar efficacy to efavirenz across a range of doses intensity, of limited duration and resolved by the end of from 25 to 200 mg [25]. The single-dose DDI assess- the study. ment in Study 2 further supports a lack of interaction, In Study 1, three of the eight participants (37.5%) with DOR AUC , C and C all without clinically 0–∞ max 24 h reported a total of ten AEs, four of which were con- meaningful changes. sidered to be related to study treatment (fatigue, 3TC and TDF are commonly administered together, without evidence of a meaningful interaction when coad- ministered [20,21]. As such, Study 2 was designed with coadministration of 3TC+TDF without evaluation of Table 1. Study population demographics each of the separate components. Data showed the lack Characteristic Study 1 (n=8) Study 2 (n=15) of a meaningful effect of DOR on either 3TC or tenofo- vir PK. Tenofovir exposure and C increased slightly max Gender (by 11% and 17%, respectively) with coadministration Male, n (%) 8 (100) 7 (46.7) of DOR. These changes are not clinically meaningful, Female, n (%) 0 8 (53.3) based on drug-interaction effects and dosing recommen- Mean age, years (range) 44.3 (36–50) 44 (23–56) dations for TDF [21]. The cause of the effect is unknown. Mean body mass index, kg/m ±sd 29.2 ±2.0 26.2 ±2.9 It has been noted that tenofovir is a substrate of P-gp Race and breast cancer-resistant protein (BCRP) transport- Asian, n (%) 0 2 (13.3) ers [21]. Atazanavir and other HIV protease inhibitors, Black or African American, n (%) 6 (75.0) 3 (20.0) White, n (%) 2 (25.0) 10 (66.7) which are P-gp and BCRP inhibitors, modestly increase 446 ©2019 International Medical Press AVT-19-OA-4508_Anderson.indd 446 AVT-19-OA-4508_Anderson.indd 446 22/11/2019 13:16:36 22/11/2019 13:16:36 Doravirine, lamivudine and tenofovir drug–drug interactions Figure 1. Plasma concentration–time profiles A B 10,000 2,000 3,000 3,000 1,000 1,000 2,500 2,500 500 10 2,000 2,000 1,500 1,500 0 24 48 72 96 120 0 6 18 30 42 54 66 78 Time, h Time, h 1,000 1,000 DOR DOR DOR + 3TC + TDF DOR+TDF 500 0 24 48 72 96 120 0 6 12 18 24 30 36 42 48 54 60 66 72 78 Time, h Time, h C D 4,000 300 1,000 3,000 50 2,000 0 6 18 30 42 54 66 78 0 6 18 30 42 54 66 78 Time, h Time, h 1,000 3TC + TDF 100 3TC + TDF DOR + 3TC + TDF DOR + 3TC + TDF 0 0 0 6 12 18 24 30 36 42 48 54 60 66 72 78 0 6 12 18 24 30 36 42 48 54 60 66 72 78 Time, h Time, h Arithmetic mean (± standard deviation) plasma concentration–time profiles of (A) single-dose doravirine (DOR) 100 mg alone and coadministered with tenofovir disoproxil fumarate (TDF) 300 mg after 14 days of once-daily TDF administration (n=8, inset=semi-log scale); (B) single-dose DOR 100 mg alone and coadministered with single doses of lamivudine (3TC) 300 mg + TDF 300 mg; (C) single-dose 3TC 300 mg following administration of 3TC 300 mg + TDF 300 mg and DOR 100 mg + 3TC 300 mg + TDF 300 mg and (D) tenofovir following administration of 3TC 300 mg + TDF 300 mg and DOR 100 mg + 3TC 300 mg + TDF 300 mg (n=15, inset=log-linear scale for (B), (C) and (D)). tenofovir plasma concentrations, although not to a data demonstrating minimal effect of TDF on DOR PK, clinically meaningful level, likely secondary to P-gp and a single-dose assessment was considered an appropriate BCRP inhibition [21,26,27]. However, in vitro observa- approach for Study 2 and is anticipated to be predictive of tions with DOR have shown that it is not an inhibitor of multiple-dose behaviour [28]. The results of these studies P-gp, indicating that interactions between DOR and P-gp did not demonstrate any substantive effect and indicate are unlikely to be the cause of the increases to plasma that, with multiple-dose administration, there would not tenofovir levels in the current study [15]. be a meaningful PK DDI between these agents. Study 1 was designed to assess the impact of TDF Administration of DOR, 3TC and TDF individually at steady state on DOR PK to maximize any poten- and in combination was generally well tolerated, pro- tial inductive or time-dependent effects of TDF. While viding further evidence of the tolerability of DOR alone Study 2 was conducted with single-dose administration and in combination with 3TC and TDF. The most com- only, no inductive effects by DOR, 3TC or tenofovir mon treatment-related AEs in both Study 1 and Study 2 were anticipated and there is no time dependence for the were headache and somnolence, which have also been PK of DOR, 3TC or tenofovir. Moreover, with Study 1 reported in DOR Phase III studies  [5,6]. The  lack of Antiviral Therapy 24.6 447 AVT-19-OA-4508_Anderson.indd 447 AVT-19-OA-4508_Anderson.indd 447 22/11/2019 13:16:37 22/11/2019 13:16:37 3TC plasma concentration, ng/ml DOR plasma concentration, nM DOR plasma 3TC plasma concentration, nM concentration, ng/ml DOR plasma concentration, nM Tenofovir plasma concentration, ng/ml DOR plasma Tenofovir plasma concentration, nM concentration, ng/ml MS Anderson et al. Table 2. Plasma PK of DOR 100 mg administered alone or with multiple-dose TDF 300 mg administered once daily for 14 days to healthy participants DOR+TDF DOR DOR+TDF/DOR PK parameter n GM 95% CI n GM 95% CI GMR 90% CI rMSE AUC , h•mM 7 33.4 25.9, 43.2 8 35.3 27.5, 45.3 0.95 0.80, 1.12 0.162 0–∞ C , nM 7 547 430, 697 8 584 463, 738 0.94 0.78, 1.12 0.171 24 h C , nM 7 1,310 965, 1,780 8 1,630 1,210, 2,190 0.80 0.64, 1.01 0.216 max T , h 7 3.0 1.0, 7.9 8 2.5 0.5, 5.0 max t , h 7 15.4 25.0 8 14.4 24.7 Root mean square error (rMSE; residual error) from the linear mixed-effect model. When multiplied by 100 approximates the within-subject % coefficient of variation b c (CV) on the raw scale. Back-transformed least-squares mean (LSM) and CI from linear mixed-effects model performed on natural log-transformed values. Median (minimum, maximum) reported for time to reach maximum plasma concentration (T ). Geometric mean (GM) and % geometric CV reported for apparent elimination max half-life (t ). AUC , area under the concentration–time curve from time 0 to infinity; C , maximum plasma concentration; C , concentration of analyte in plasma 1/2 0–∞ max 24 h 24 h after administration; DOR, doravirine; GMR, geometric mean ratio; PK, pharmacokinetic; TDF, tenofovir disoproxil fumarate. Table 3. Plasma PK of DOR 100 mg administered alone or with single-dose TDF 300 mg and 3TC 300 mg to healthy participants DOR+3TC+TDF DOR DOR+3TC+TDF/DOR PK parameter n GM 95% CI n GM 95% CI GMR 90% CI Intra-subject %CV AUC , h•mM 15 37.7 28.7, 49.4 15 39.1 31.5, 48.6 0.96 0.87, 1.06 15.2 0–∞ C , nM 15 507 332, 774 15 541 390, 750 0.94 0.83, 1.06 19.6 24 h C , nM 15 2,030 1,720, 2,400 15 2,090 1,810, 2,420 0.97 0.88, 1.07 15.1 max T , h 15 2.0 1.0, 6.0 15 3.0 1.0, 4.0 max t , h 15 13.5 40.6 15 13.8 31.9 a 2 2 b Estimated based on the elements of the variance-covariance matrix as: coefficient of variation (CV; %) = 100*sqrt[(sA + sB - 2*sAB)/2]. Back-transformed least-squares mean (LSM) and CI from linear mixed-effects model performed on natural log-transformed values. Median (minimum, maximum) reported for time to reach maximum plasma concentration (T ). Geometric mean (GM) and % geometric CV reported for apparent elimination half-life (t ). AUC , area under max 1/2 0–∞ the concentration–time curve from time 0 to infinity; C , maximum plasma concentration; C , concentration of analyte in plasma 24 h after administration; max 24 h DOR, doravirine; GMR, geometric mean ratio; PK, pharmacokinetic; TDF, tenofovir disoproxil fumarate; 3TC, lamivudine. Table 4. Plasma PK of 3TC and tenofovir following single-dose administration of 3TC 300 mg + TDF 300 mg or DOR 100 mg + 3TC 300 mg + TDF 300 mg to healthy participants DOR+3TC+TDF 3TC+TDF DOR+3TC+TDF/3TC+TDF PK parameter n GM 95% CI n GM 95% CI GMR 90% CI for GMR Intra-subject %CV 3TC AUC , h•ng/ml 15 14,200 12,400, 16,200 15 15,000 13,800, 16,500 0.94 0.88, 1.00 9.7 0–∞ C , ng/ml 15 2,910 2,460, 3,450 15 3,150 2,760, 3,600 0.92 0.81, 1.05 19.4 max T , h 15 1.00 1.0, 2.0 15 1.00 0.5, 2.0 max t , h 15 15.9 57.6 15 15.7 32.2 Tenofovir AUC , h•ng/ml 15 2,790 2,470, 3,150 15 2,500 2,090, 2,990 1.11 0.97, 1.28 20.5 0–∞ C , ng/ml 15 338 286, 400 15 289 237, 352 1.17 0.96, 1.42 29.7 max T , h 15 1.0 0.5, 2.0 15 1.00 0.5, 1.0 max t , h 15 20.9 18.5 15 19.7 12.6 a 2 2 b Estimated based on the elements of the variance-covariance matrix as: coefficient of variation (CV; %) = 100*sqrt[(sA + sB - 2*sAB)/2]. Back-transformed least-squares mean (LSM) and CI from linear mixed-effects model performed on natural log-transformed values. Median (minimum, maximum) reported for time to reach maximum plasma concentration (T ). Geometric mean (GM) and % geometric CV reported for apparent elimination half-life (t ). AUC , area under the max 1/2 0–∞ concentration–time curve from time 0 to infinity; C , maximum plasma concentration; DOR, doravirine; GMR, geometric mean ratio; PK, pharmacokinetic; TDF, max tenofovir disoproxil fumarate; 3TC, lamivudine. DDIs between DOR and 3TC+TDF supports the fixed- used in a recently reported Phase III study (discussed in dose, three-drug, single-tablet regimen (MK-1439A the Introduction) [6]. [DOR 100 mg/3TC 300  mg/TDF  300  mg]) that has In summary, multiple doses of TDF coadministered been developed [29], and which was the formulation with a single dose of DOR did not have a clinically 448 ©2019 International Medical Press AVT-19-OA-4508_Anderson.indd 448 AVT-19-OA-4508_Anderson.indd 448 22/11/2019 13:16:37 22/11/2019 13:16:37 Doravirine, lamivudine and tenofovir drug–drug interactions Figure 2. Individual plasma pharmacokinetic ratios A B 1.4 2.0 1.3 1.2 1.1 1.0 0.9 1.0 0.8 0.7 0.6 0.5 0.5 AUC C C AUC C C 0–∞ 24 h max 0–∞ 24 h max C D 3.5 1.4 3.0 1.2 2.5 2.0 1.0 1.5 0.8 1.0 0.6 AUC C AUC C 0–∞ max 0–∞ max Individual ratios GMR with 90% CI Individual plasma pharmacokinetic ratios and corresponding geometric mean ratios with 90% CIs for (A) single-dose doravirine (DOR) 100 mg with and without multiple-dose tenofovir disoproxil fumarate (TDF) 300 mg (n=8), (B) single-dose DOR 100 mg with and without single-dose lamivudine (3TC) 300 mg + TDF 300 mg (n=15), (C) 3TC after administration of single-dose 3TC 300 mg + TDF 300 mg, with DOR 100 mg versus without DOR (n=15) and (D) tenofovir after administration of 3TC 300 mg + TDF 300 mg, with DOR 100 mg versus without DOR (n=15). AUC , area under the concentration–time curve from time 0 to infinity; C , maximum 0–∞ max concentration; C , concentration of analyte in plasma 24 h after administration. 24 h meaningful effect on the PK of DOR. DOR, 3TC and assistance was funded by Merck Sharp & Dohme Corp., tenofovir PK were similar when administered alone or a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. coadministered. Consequently, coadministration of the three drugs without dose adjustment is supported. Disclosure statement This research was funded by Merck Sharp & Dohme Acknowledgements Corp., a subsidiary of Merck & Co., Inc., Kenilworth, The authors would like to thank the trial staff and NJ, USA. JG, LF, KLY, IT and MI are employees of participants. In addition, the authors would like to thank Merck Sharp & Dohme Corp., a subsidiary of Merck Paul Fackler and Marty Behm (both formerly Merck & & Co., Inc., Kenilworth, NJ, USA, and may own stock Co., Inc., Kenilworth, NJ, USA) for their help with the and/or hold stock options in Merck & Co., Inc., Kenil- study. Medical writing and editorial assistance, under the worth, NJ, USA. MSA, CR, YG and RL were employ- direction of the authors, was provided by Annette Smith ees of Merck Sharp & Dohme Corp., a subsidiary of of CMC AFFINITY, a division of McCann Health Medi- Merck & Co., Inc., Kenilworth, NJ, USA at the time the cal Communications Ltd., Macclesfield, UK, in accordance study was conducted. WKK has no conflicts of interest with Good Publication Practice (GPP3) guidelines. This to disclose. 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Accepted 2 June 2019; published online 21 August 2019 450 ©2019 International Medical Press AVT-19-OA-4508_Anderson.indd 450 AVT-19-OA-4508_Anderson.indd 450 22/11/2019 13:16:37 22/11/2019 13:16:37

Journal

Antiviral Therapy – SAGE

Published: Aug 1, 2019

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