Fostemsavir and ethinyl estradiol drug interaction: Clinical recommendations for co-administration.

OBJECTIVES: Fostemsavir, a prodrug of temsavir, is indicated for heavily treatment-experienced adults with multidrug-resistant HIV-1 infection, antiretroviral (ARV) intolerance, or safety considerations. Understanding drug-drug interactions (DDIs) is important in individuals taking fostemsavir with hormonal contraceptives or menopausal or gender-affirming hormonal therapies. METHODS: Effect of temsavir (active moiety) on the pharmacokinetics of ethinyl estradiol (EE) and norethindrone (NET) was evaluated in an open-label, single-sequence, four-cycle, four-treatment study in 26 healthy female participants (study 206279, NCT02480881). Relevant ARV-contraceptive interaction studies and guideline recommendations were reviewed; that information was then applied to other contraceptive methods and hormone-based therapies to predict the impact of fostemsavir co-administration. RESULTS: Temsavir increased EE concentrations by 40% and had no effect on NET concentrations. Fostemsavir co-administration with hormone therapy is not expected to impact hormone treatment efficacy. Fostemsavir did not impact progestin; therefore, progestin-only and non-hormonal contraceptives will not be impacted by fostemsavir. Recommendations for co-administration of fostemsavir and hormonal contraceptives or menopausal or gender-affirming hormone therapies are based upon known and predicted DDIs, ensuring adequate hormonal concentrations to maintain the target effect. CONCLUSIONS: Applying the results of Study 206279 and other relevant ARV-contraceptive studies, we recommend that when co-administering fostemsavir with combined oral contraceptives (COCs) and other oestrogen-based therapies, EE dose should not exceed 30 µg or equivalent, and caution is advised in the case of individuals with risk factors for thromboembolic events. Other oestrogen-based therapies may be co-administered with fostemsavir, with monitoring of oestrogen concentrations and appropriate dose adjustments. No impact of fostemsavir on COC efficacy is expected.

Pharmacokinetics of Temsavir, the Active Moiety of the HIV-1 Attachment Inhibitor Prodrug, Fostemsavir, Coadministered with Cobicistat, Etravirine, Darunavir/Cobicistat, or Darunavir/Ritonavir with or without Etravirine in Healthy Participants.

Fostemsavir is a prodrug of temsavir, a first-in-class attachment inhibitor that binds directly to HIV-1 gp120, preventing initial viral attachment and entry into host CD4+ T cells with demonstrated efficacy in phase 2 and 3. Temsavir is a P-glycoprotein and breast cancer resistance protein (BCRP) substrate; its metabolism is mediated by esterase and CYP3A4 enzymes. Drugs that induce or inhibit CYP3A, P-glycoprotein, and BCRP may affect temsavir concentrations. Understanding potential drug-drug interactions (DDIs) following fostemsavir coadministration with antiretrovirals approved for HIV-1-infected treatment-experienced patients, including darunavir plus cobicistat (DRV/c) or DRV plus low-dose ritonavir (DRV/r) and etravirine, is clinically relevant. Open-label, single-sequence, multiple-dose, multicohort DDI studies were conducted in healthy participants (n = 46; n = 32). The primary objective was to assess the effects of DRV/r, etravirine, DRV/r plus etravirine, cobicistat, and DRV/c on temsavir systemic exposures; safety was a secondary objective. Compared with fostemsavir alone, coadministration with DRV/r increased the temsavir maximum observed plasma concentration (Cmax), area under the concentration-time curve in one dosing interval (AUCtau), and plasma trough concentration (Ctau) by 52%, 63%, and 88%, respectively, while etravirine decreased the temsavir Cmax, AUCtau, and Ctau by ∼50% each. DRV/r plus etravirine increased the temsavir Cmax, AUCtau, and Ctau by 53%, 34%, and 33%, respectively. Compared with fostemsavir alone, coadministration with cobicistat increased the temsavir Cmax, AUCtau, and Ctau by 71%, 93%, and 136%, respectively; DRV/c increased the temsavir Cmax, AUCtau, and Ctau by 79%, 97%, and 124%, respectively. Fostemsavir with all combinations was generally well tolerated. No dose adjustment is required for fostemsavir when coadministered with strong CYP3A inhibitors, P-glycoprotein inhibitors, and modest inducers, including regimens with DRV/r, DRV/c, cobicistat, etravirine, and DRV/r plus etravirine based on the therapeutic margin for temsavir (ClinicalTrials.gov registration no. NCT02063360 and NCT02277600).

Pharmacokinetics, metabolism and excretion of radiolabeled fostemsavir administered with or without ritonavir in healthy male subjects.

The pharmacokinetics, elimination, and metabolism of fostemsavir (FTR), a prodrug of the HIV-1 attachment inhibitor temsavir (TMR), were investigated in healthy volunteers. FTR was administered with and without ritonavir (RTV), a protease inhibitor previously shown to boost TMR exposures. In vitro studies were also used to identify the enzymes responsible for the metabolism of TMR.Total recovery of the administered dose ranged from 78% to 89%. Approximately 44% to 58% of the dose was excreted in urine, 20%-36% in faeces, and 5% in bile, as TMR and metabolites. RTV had no effect on the recovery of radioactivity in any matrix.Compared to FTR alone, pre-treatment of subjects with RTV increased the exposure of TMR by ∼66% and reduced the exposure of plasma total radioactivity by ∼68%.The major route of TMR elimination was through biotransformation. TMR, M28 (N-dealkylation), and M4 (amide hydrolysis) were the major circulating components in plasma. Pre-treatment with RTV increased the amount of TMR present, decreased the amount of circulating M28, and M4 was unchanged.CYP3A4 metabolism accounted for 21% of the dose, forming multiple oxidative metabolites. This pathway was inhibited by coadministration of RTV.

Methadone and buprenorphine pharmacokinetics and pharmacodynamics when coadministered with fostemsavir to opioid-dependent, human immunodeficiency virus seronegative participants.

AIMS: Regional human immunodeficiency virus (HIV) prevalence rates are high in people with history of injection drug use, including those managed with maintenance opioids. Fostemsavir (FTR) is an oral prodrug of temsavir, a first-in-class attachment inhibitor that binds HIV-1 gp120, preventing initial HIV attachment and entry into host immune cells. Here we determine the impact of FTR on the pharmacokinetics of opioids methadone (MET: R-, S- and total) or buprenorphine and norbuprenorphine (BUP and norBUP) when coadministered. METHODS: Study 206216 (NCT02666001) was a Phase I, open-label study, assessing the effect of FTR 600 mg (extended-release formulation) twice daily on pharmacokinetics of MET or BUP and norBUP, in non-HIV-infected participants on stable maintenance therapy with MET (40-120 mg; n = 16) or BUP plus naloxone (8-24 mg plus 2-6 mg; n = 16); pharmacodynamic response was assessed using standard opioid rating scales. RESULTS: Following coadministration with FTR, dose-normalized MET (R-, S- and total) exposures (maximum concentration in plasma, area under the plasma concentration-time curve over the dosing interval and concentration in plasma at 24 hours) increased 9-15% and BUP and norBUP exposures increased 24-39%. The 90% confidence interval ranges for MET (1.01-1.21) and BUP and norBUP (1.03-1.69) were within respective no-effect ranges (0.7-1.43 and 0.5-2.0). Opioid pharmacodynamic scores were similar with and without MET/BUP with no symptoms of withdrawal/overdose; no new safety signal for FTR when combined with a stable opioid regimen. CONCLUSIONS: FTR did not impact MET and had no clinically significant impact on BUP pharmacokinetics. Standardized assessments of opioid pharmacodynamics were unchanged throughout FTR administration with MET or BUP. FTR can be administered with MET or BUP without dose adjustment.

Safety, pharmacokinetics and pharmacological effects of the selective androgen receptor modulator, GSK2881078, in healthy men and postmenopausal women.

AIM: Selective androgen receptor modulators (SARMs) induce anabolic effects on muscle without the adverse effects of androgenic steroids. In this first-in-human study, we report the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics of the SARM GSK2881078. METHODS: In Part A, healthy young men (n = 10) received a single dose of study drug (0 mg, 0.05 mg, 0.1 mg, 0.2 mg GSK2881078 or matching-placebo). In Part B, repeat-dose cohorts in men (n = 65) were 0.05 mg, 0.2 mg then 0.08 mg, 0.24 mg, 0.48 mg, 0.75 mg, or placebo; in women (n = 24) they were 0.24 mg, 0.35 mg, or placebo (7 days for 0.5 mg, 14 days for other doses). RESULTS: PK analysis showed dose-proportional increases in exposure and a long >100-h half-life. No significant effects on vital signs, electrocardiograms, cardiac telemetry or standard clinical laboratory studies were observed. A dose-response effect was observed on lowering both high-density lipoprotein and sex hormone-binding globulin. In females at 0.35 mg, differences from placebo were -0.518 (95% confidence interval: -0.703, -0.334) mmol l-1 and -39.1 (-48.5, -29.7) nmol l-1 , respectively. Women showed greater sensitivity to these parameters at lower doses than men. Drug-related adverse events (AEs) were mild. One woman developed a drug rash and was withdrawn. Two men had elevated creatine phosphokinase after physical exertion during follow-up. A serious AE occurred in a subject on placebo. CONCLUSIONS: These data demonstrate pharmacodynamic effects with acceptable tolerability and support further clinical evaluation of this SARM.

Darapladib, a lipoprotein-associated phospholipase A2 inhibitor, in diabetic macular edema: a 3-month placebo-controlled study.

PURPOSE: To investigate the potential of lipoprotein-associated phospholipase A2 inhibition as a novel mechanism to reduce edema and improve vision in center-involved diabetic macular edema (DME). DESIGN: Prospective, multicenter, randomized, double-masked, placebo-controlled phase IIa study. PARTICIPANTS: Fifty-four center-involved DME patients randomized 2:1 to receive darapladib (n = 36) or placebo (n = 18). METHODS: Darapladib 160 mg or placebo monotherapy was administered orally once daily for 3 months, and patients were followed up monthly for 4 months. MAIN OUTCOME MEASURES: Mean change from baseline in best-corrected visual acuity (BCVA) and the center subfield and center point of the study eye at month 3 as determined by spectral-domain optical coherence tomography. RESULTS: Five patients in the study received intravitreal anti-vascular endothelial growth factor rescue therapy before the day 90 assessment, 2 of 36 (6%) in the darapladib arm and 3 of 18 (17%) in the placebo arm. Administration of 160 mg darapladib for 3 months resulted in statistically significant mean improvements, from baseline to month 3, in BCVA of 4.1 Early Treatment Diabetic Retinopathy Study (ETDRS) letters (95% confidence interval [CI], 2.3-5.8) and of 57 µm in central subfield thickness (95% CI, -84 to -30) in the study eyes. An increase in BCVA of 1.7 ETDRS letters (95% CI, -1.0 to 4.4) and a decrease in center subfield thickness of 34 µm (95% CI, -75 to 6.8) for the placebo group were not significant. No ocular severe adverse events (SAEs) or SAEs considered related to darapladib were reported. One SAE of myocardial infarction, not considered related to darapladib, was reported, and 1 SAE of severe diarrhea was reported in a placebo patient, subsequently withdrawn from the study. Study eye ocular adverse events (AEs) and nonocular AEs were similar between treatment groups. CONCLUSIONS: Once-daily oral darapladib administered for 3 months demonstrated modest improvements in vision and macular edema that warrant additional investigation of this novel lipoprotein-associated phospholipase A2 inhibitory mechanism for the treatment of DME.

The pharmacokinetics and safety of darapladib in subjects with severe renal impairment.

AIM: Darapladib is a potent and reversible orally active inhibitor of lipoprotein-associated phospholipase A2 (Lp-PLA2 ). The aim of the study was to assess the effects of severe renal impairment on the pharmacokinetics and safety/tolerability of darapladib compared with normal renal function. METHODS: This was an open label, parallel group study of darapladib following 10 day once daily 160 mg oral dosing in subjects with normal (n = 8) and severe renal impairment (estimated glomerular filtration rate <30 ml min(-1) 1.73 m(-2) , n = 8). Plasma concentrations of total and unbound darapladib as well as total darapladib metabolites were determined in samples obtained over 24 h on day 10. RESULTS: Plasma concentrations of total and unbound darapladib as well as all three metabolites were higher in subjects with severe renal impairment. Area under the plasma concentration vs. time curve between time zero and 24 h (AUC(0,24 h) and maximum plasma concentration (Cmax ) of total darapladib in severely renally impaired subjects were 52% and 59% higher than those in the matched healthy subjects, respectively. Similar results were found with the darapladib metabolites. Darapladib was highly plasma protein bound with 0.047% and 0.034% unbound circulating in plasma in severely renally impaired and healthy subjects, respectively. Unbound plasma darapladib exposures were more than two-fold higher in severely renally impaired subjects than in healthy controls. Adverse events (AE) were reported in 38% of healthy subjects and 75% of severely renally impaired subjects, most of which were mild or moderate in intensity. CONCLUSIONS: The results of this study showed that darapladib exposure was increased in subjects with severe renal impairment compared with healthy controls. However, darapladib was generally well tolerated in both groups.

Disposition and metabolism of darapladib, a lipoprotein-associated phospholipase A2 inhibitor, in humans.

The absorption, metabolism, and excretion of darapladib, a novel inhibitor of lipoprotein-associated phospholipase A2, was investigated in healthy male subjects using [(14)C]-radiolabeled material in a bespoke study design. Disposition of darapladib was compared following single i.v. and both single and repeated oral administrations. The anticipated presence of low circulating concentrations of drug-related material required the use of accelerator mass spectrometry as a sensitive radiodetector. Blood, urine, and feces were collected up to 21 days post radioactive dose, and analyzed for drug-related material. The principal circulating drug-related component was unchanged darapladib. No notable metabolites were observed in plasma post-i.v. dosing; however, metabolites resulting from hydroxylation (M3) and N-deethylation (M4) were observed (at 4%-6% of plasma radioactivity) following oral dosing, indicative of some first-pass metabolism. In addition, an acid-catalyzed degradant (M10) resulting from presystemic hydrolysis was also detected in plasma at similar levels of ∼5% of radioactivity post oral dosing. Systemic exposure to radioactive material was reduced within the repeat dose regimen, consistent with the notion of time-dependent pharmacokinetics resulting from enhanced clearance or reduced absorption. Elimination of drug-related material occurred predominantly via the feces, with unchanged darapladib representing 43%-53% of the radioactive dose, and metabolites M3 and M4 also notably accounting for ∼9% and 19% of the dose, respectively. The enhanced study design has provided an increased understanding of the absorption, distribution, metabolism and excretion (ADME) properties of darapladib in humans, and substantially influenced future work on the compound.

An effect of moderate hepatic impairment on the pharmacokinetics and safety of darapladib.

AIM/METHODS: This was a phase 1, open label, non-randomized study designed to assess the pharmacokinetics and safety/tolerability of 10 consecutive once daily 40 mg oral doses of darapladib in subjects with moderate hepatic impairment (n = 12) compared with matched healthy volunteers (n = 12). RESULTS: For total darapladib, a small increase in total and peak exposure was observed in the subjects with moderate hepatic impairment compared with the subjects with normal hepatic function. The area under the plasma concentration-time curve during a dosing interval of duration τ (AUC(0,τ), geometric mean 223 ng ml(-1) h [90% CI 158, 316 ng ml(-1 ) h], in moderate hepatic impaired subjects, vs. geometric mean 186 ng ml(-1 ) h [90% CI 159, 217 ng ml(-1 ) h], in healthy subjects) and maximum concentration (Cmax ) were 20% and 7% higher, respectively, in the subjects with moderate hepatic impairment than in the healthy control subjects and there was no change in time to maximum concentration (tmax ). Protein binding was performed to measure the amount of unbound drug vs. bound. Steady-state was achieved by day 10 for darapladib and its metabolites (M4, M3 and M10). Darapladib was generally well tolerated, with adverse events (AEs) reported by seven subjects in the hepatic impairment group and three subjects in the healthy matched group (five and one of which were drug-related AEs, respectively). The most common AEs were gastrointestinal. These AEs were mostly mild to moderate and there were no deaths, serious AEs or withdrawals due to AEs. CONCLUSIONS: The results of this phase 1 study show that darapladib (40 mg) is well tolerated and its pharmacokinetics remain relatively unchanged in patients with moderate hepatic impairment.

A Quantitative Clinical Pharmacology-Based Framework For Model-Informed Vaccine Development.

Historically, vaccine development and dose optimization have followed mostly empirical approaches without clinical pharmacology and model-informed approaches playing a major role, in contrast to conventional drug development. This is attributed to the complex cascade of immunobiological mechanisms associated with vaccines and a lack of quantitative frameworks for extracting dose-exposure-efficacy-toxicity relationships. However, the Covid-19 pandemic highlighted the lack of sufficient immunogenicity due to suboptimal vaccine dosing regimens and the need for well-designed, model-informed clinical trials which enhance the probability of selection of optimal vaccine dosing regimens. In this perspective, we attempt to develop a quantitative clinical pharmacology-based approach that integrates vaccine dose-efficacy-toxicity across various stages of vaccine development into a unified framework that we term as model-informed vaccine dose-optimization and development (MIVD). We highlight scenarios where the adoption of MIVD approaches may have a strategic advantage compared to conventional practices for vaccines.

Population Pharmacokinetics of Bepirovirsen in Healthy Participants and Participants with Chronic Hepatitis B Virus Infection: Results from Phase 1, 2a, and 2b Studies.

INTRODUCTION: Bepirovirsen is a novel antisense oligonucleotide in development for chronic hepatitis B virus (HBV) infection therapy. Understanding the impact that clinical characteristics may have on bepirovirsen exposure is important for determining efficacious and well-tolerated dosing regimens. This analysis evaluated demographics and clinical characteristics associated with bepirovirsen exposure using a population pharmacokinetic (PK) analysis. METHODS: Population PK analyses were conducted using pooled data from three phase 1/2 clinical studies (NCT03020745/NCT02981602/NCT04449029) to construct a structural PK model for bepirovirsen that adequately described plasma concentration-time profiles and identify covariates that affect systemic exposure. The final population PK model was used to simulate bepirovirsen exposure measures to inform exposures at different dose levels and within different subpopulations. RESULTS: Bepirovirsen PK data were well-described by a linear, three-compartment model with first-order absorption and absorption delay. Chronic HBV infection status, body weight, and Asian versus non-Asian race were key covariates included in the final model. Visual inspection of correlation scatter plots confirmed general agreement between observed and predicted data from the studies. In simulations, bepirovirsen systemic exposure was dosed proportionally and predicted to be almost completely washed out by 12 weeks following the final 300-mg dose. Differences in body weight, Asian race, or disease status did not result in clinically relevant differences in exposure. CONCLUSIONS: This analysis demonstrated that the linear three-compartmental model accurately described bepirovirsen PK data. The lack of clinically relevant differences seen in exposure indicate that dose adjustments are not recommended for bepirovirsen based on demographics or clinical characteristics.

Considerations for Industry-Preparing for the FDA Model-Informed Drug Development (MIDD) Paired Meeting Program.

A recent industry perspective published in this journal describes the benefits received by drug companies from participation in the MIDD Pilot Program. Along with the primary objectives of supporting good decision-making in drug development, there were substantial savings in time and development costs. Furthermore, many sponsors reported qualitative benefits such as new learnings and clarity on MIDD strategies and methodology that could be applied to other development programs. Based on the success of the Pilot Program, the FDA recently announced the continuation of the MIDD Paired Meeting Program as part of the Prescription Drug User Fee Act (PDUFA VII). In this report, we describe the collective experiences of industry participants in the MIDD Program to date, including all aspects of the process from meeting request submission to follow-up actions. The purpose is to provide future participants with information to optimize the value of the MIDD Program.

Model-Based Dose Selection of Fostemsavir for Pediatric Populations With Multidrug-Resistant HIV-1 and Relative Bioavailability Assessment in Healthy Adults.

Fostemsavir, a prodrug of the first-in-class HIV-1 attachment inhibitor temsavir, is approved for the treatment of multidrug-resistant HIV-1 in adults; its use in pediatric populations is currently being studied. Population pharmacokinetic modeling across pediatric weight bands was used to guide pediatric fostemsavir dose selection. Dosing simulations demonstrated that twice-daily fostemsavir 600-mg (adult dose) and 400-mg doses met safety and efficacy criteria for 35 kg or greater and 20 or greater to less than 35 kg pediatric weight bands, respectively. Temsavir relative bioavailability of 2 low-dose fostemsavir extended-release formulations (3 × 200 mg; formulations A and B) and reference formulation (600 mg extended release) was assessed in a 2-part, open-label, randomized, crossover study in healthy adults. Part 1 (N = 32) compared single-dose temsavir relative bioavailability, and Part 2 (N = 16) evaluated the impact of fed versus fasted conditions using the selected low-dose formulation. Temsavir geometric mean ratios for the area under the plasma concentration-time curve from time zero to infinity and maximum concentration for formulation B were bioequivalent to the reference formulation. Temsavir maximum concentration for formulation B was similar in fed and fasted states, but area under the plasma concentration-time curve from time zero to infinity geometric mean ratio was increased under fed conditions, consistent with previous results in adults. These analyses demonstrated efficient pediatric dose selection using a model-based approach.

Opportunities and Challenges of Disease Progression Modeling in Drug Development - An IQ Perspective.

Disease progression modeling (DPM) represents an important model-informed drug development framework. The scientific communities support the use of DPM to accelerate and increase efficiency in drug development. This article summarizes International Consortium for Innovation & Quality (IQ) in Pharmaceutical Development mediated survey conducted across multiple biopharmaceutical companies on challenges and opportunities for DPM. Additionally, this summary highlights the viewpoints of IQ from the 2021 workshop hosted by the US Food and Drug Administration (FDA). Sixteen pharmaceutical companies participated in the IQ survey with 36 main questions. The types of questions included single/multiple choice, dichotomous, rank questions, and open-ended or free text. The key results show that DPM has different representation, it encompasses natural disease history, placebo response, standard of care as background therapy, and can even be interpreted as pharmacokinetic/pharmacodynamic modeling. The most common reasons for not implementing DPM as frequently seem to be difficulties in internal cross-functional alignment, lack of knowledge of disease/data, and time constraints. If successfully implemented, DPM can have an impact on dose selection, reduction of sample size, trial read-out support, patient selection/stratification, and supportive evidence for regulatory interactions. The key success factors and key challenges of disease progression models were highlighted in the survey and about 24 case studies across different therapeutic areas were submitted from various survey sponsors. Although DPM is still evolving, its current impact is limited but promising. The success of such models in the future will depend on collaboration, advanced analytics, availability of and access to relevant and adequate-quality data, collaborative regulatory guidance, and published examples of impact.

Evaluation of the pharmacokinetic drug-drug interaction between the antiretroviral agents fostemsavir and maraviroc: a single-sequence crossover study in healthy participants.

BACKGROUND: Fostemsavir is an oral prodrug of temsavir, a first-in-class attachment inhibitor that binds HIV-1 gp120, preventing initial HIV attachment and entry into host immune cells. OBJECTIVE: The pharmacokinetic interaction was determined between temsavir and maraviroc, a CCR5 allosteric inhibitor indicated for CCR5-tropic HIV-1 that may be co-administered with fostemsavir as part of combination antiretroviral therapy in heavily treatment-experienced adults with multidrug-resistant HIV-1 infection. METHODS: This was a Phase 1, open-label, single-sequence, 3-period crossover study evaluating the effect of fostemsavir on maraviroc pharmacokinetics and the effect of maraviroc on temsavir pharmacokinetics (ClinicalTrials.gov, NCT02480894). Fourteen healthy participants received fostemsavir 600 mg twice daily (BID) for 4 days in Period 1 (followed by a 3-day washout), maraviroc 300 mg BID for 5 days in Period 2, and fostemsavir 600 mg BID with maraviroc 300 mg BID for 7 days in Period 3. Study drugs were administered orally with a standard meal. RESULTS: Following fostemsavir and maraviroc co-administration, maraviroc area under the plasma concentration-time curve over the dosing interval (AUCτ) increased 25% (from 1914 to 2382 ng.h/mL) and maraviroc plasma concentration at the end of the dosing interval (Ctrough) increased 37% (from 36.5 to 49.9 ng/mL), but there was no change in maximum observed concentration (Cmax). Following fostemsavir and maraviroc co-administration, temsavir AUCτ and Cmax increased 10-13% and Ctrough decreased 10%. CONCLUSIONS: Co-administration of fostemsavir and maraviroc did not result in clinically relevant changes in maraviroc or temsavir exposure. Fostemsavir and maraviroc may be co-administered without dose adjustment of either antiretroviral agent.

Effect of Renal and Hepatic Impairment on the Pharmacokinetics of Temsavir, the Active Moiety of Fostemsavir.

The oral prodrug fostemsavir (GSK3684394, formerly BMS-663068) is an antiretroviral treatment for HIV-1. Fostemsavir is metabolized to its active moiety, temsavir, a first-in-class HIV-1 attachment inhibitor that binds to the viral envelope glycoprotein 120. Long-term antiretroviral therapy, the resulting longer life expectancy, and/or certain coinfections can increase the risk of chronic liver and kidney disease in HIV-1-infected individuals. Two studies were conducted to collectively evaluate the impact of renal and hepatic impairment on temsavir pharmacokinetics (PK) and safety following a single dose of a 600-mg extended-release fostemsavir tablet. There was no clinically meaningful effect of renal or hepatic impairment on temsavir PK, although renal clearance decreased with increasing renal impairment from moderate to severe, and exposure (maximum concentration and area under the plasma concentration-time curve from time 0 to infinity) tended to increase with increasing severity of hepatic impairment. No clinically meaningful effect of hemodialysis on temsavir PK parameters was observed. Fostemsavir was generally safe and well tolerated by treated subjects. Most adverse events (AEs) were mild, with the exception of 1 patient in the renal impairment study who discontinued due to 2 serious AEs unrelated to the study drug. No other treatment-emergent serious AEs occurred, and no other AEs leading to discontinuation were reported. Overall, these results suggest that fostemsavir can be used without dose modification in subjects with mild to severe renal impairment, including those with end-stage renal disease on hemodialysis, and in subjects with mild to severe hepatic impairment.

Effects of rifampicin (rifampin) on the pharmacokinetics and safety of ambrisentan in healthy subjects: a single-sequence, open-label study.

BACKGROUND: Ambrisentan is a once-daily, endothelin (ET) type A receptor-selective antagonist approved for the treatment of pulmonary arterial hypertension. Ambrisentan is primarily metabolized by glucuronidation and undergoes cytochrome P450 (CYP)-mediated oxidation to a lesser extent. OBJECTIVE: To assess the effects of rifampicin (rifampin), a potent inducer of CYP3A4 and inhibitor of organic anion transporter polypeptides (OATPs), on the steady-state pharmacokinetics, safety and tolerability of ambrisentan. METHODS: This was a 14-day, single-sequence, open-label study that was conducted in 24 healthy adults. Subjects were administered oral doses of ambrisentan (10 mg) once daily on days 1 through 5 and were then co-administered ambrisentan (10 mg) plus rifampicin (600 mg) once daily on days 6 through 13. The steady-state pharmacokinetics of ambrisentan and its oxidative metabolite 4-hydroxymethyl ambrisentan were determined in the absence and presence of repeated administration of rifampicin. The main outcome measure was the analysis of ambrisentan pharmacokinetics (area under the plasma concentration-time curve during a dosage interval [AUC(τ)], maximum plasma drug concentration [C(max)] and minimum plasma drug concentration [C(min)]) for steady-state ambrisentan alone (day 5) as compared with steady-state ambrisentan plus steady-state rifampicin (day 13). Adverse events (AEs), ECG recordings, vital signs and clinical laboratory parameters were monitored throughout the study and at follow-up. RESULTS: A transient increase (+87% [95% CI 79, 95]) in ambrisentan steady-state systemic exposure (AUC(τ)) was observed during the first 2 days of rifampicin co-administration. However, in the presence of steady-state rifampicin, ambrisentan C(max) and AUC(τ) values were similar (+2% [95% CI -7, 12] and -4% [-9, 2], respectively) to those observed for ambrisentan alone. Relative systemic exposure of 4-hydroxymethyl ambrisentan was unaffected by either acute or steady-state rifampicin. No serious AEs or AEs leading to withdrawal were reported and there were no clinically significant changes in vital signs, ECG recordings or clinical laboratory parameters with co-administration of ambrisentan and rifampicin. CONCLUSION: Steady-state rifampicin had no clinically relevant effects on the steady-state pharmacokinetics of ambrisentan. The overall safety profile of ambrisentan was similar in the presence and absence of rifampicin. No dose adjustment of ambrisentan should be required when it is co-administered with rifampicin, a strong inducer of CYP3A4 activity and inhibitor of OATPs.

Effects of Temsavir, Active Moiety of Antiretroviral Agent Fostemsavir, on QT Interval: Results From a Phase I Study and an Exposure-Response Analysis.

Fostemsavir, a prodrug of human immunodeficiency virus attachment inhibitor temsavir (TMR), is in phase III development in combination with other antiretroviral agents for the treatment of human immunodeficiency virus type I (HIV-1) infection in heavily treatment-experienced adults with multidrug-resistant HIV-1 infection for whom it is otherwise not possible to construct a suppressive antiviral regimen due to resistance, intolerance, or safety considerations. The proarrhythmic potential of fostemsavir was studied in a thorough QT study and exposure-response modeling was performed at therapeutic and supratherapeutic concentrations of TMR. Fostemsavir 1,200 mg b.i.d. did not result in a clinically meaningful change from placebo in baseline-adjusted Fridericia-corrected QTc (ddQTcF); however, at a supratherapeutic dose of 2,400 mg b.i.d., the upper bound of the two-sided 90% confidence interval (CI) of ddQTcF was 13.2 msec, exceeding the clinically important 10 msec threshold. A linear model of ddQTcF as a function of TMR plasma concentrations described these observations. Based on simulations with this model, TMR concentrations up to 7,500 ng/mL are expected to have an upper 90% CI bound for QTcF ≤ 10 msec. This concentration is 4.2-fold higher than the geometric mean TMR peak plasma concentration (Cmax ) of 1,770 ng/mL in heavily treatment-experienced HIV-1 infected patients administered fostemsavir 600 mg b.i.d. in the phase III BRIGHTE study (NCT02362503).

Effect of ketoconazole on the pharmacokinetic profile of ambrisentan.

Ambrisentan is an endothelin type A (ET(A))-selective receptor antagonist that is metabolized primarily by glucuronidation but also undergoes oxidative metabolism by CYP3A4. The potential for ketoconazole, the archetypal strong inhibitor of CYP3A4, to alter the pharmacokinetic profile of ambrisentan and its oxidative metabolite, 4-hydroxymethyl ambrisentan, was assessed in an open-label, nonrandomized, 2-period, single-sequence study in 16 healthy men. Participants received a single dose of ambrisentan 10 mg alone and after 4 days of ketoconazole 400 mg administered once daily. In the presence of multiple doses of ketoconazole, single-dose ambrisentan AUC(0-infinity) estimate was increased by 35.3%, whereas C(max) was increased by 20.0%. For the 4-hydroxymethyl ambrisentan metabolite, AUC(0-infinity) estimate was decreased by 4.0%, whereas C(max) was decreased by 16.5%. Concomitant administration of ambrisentan and ketoconazole was well tolerated. In summary, ketoconazole had no clinically significant effect on the pharmacokinetics or safety profile of ambrisentan; therefore, no changes in ambrisentan dose should be necessary when the drug is administered concomitantly with known CYP3A4 inhibitors.

A Phase 1 Randomized, Placebo-Controlled Study Assessing the Pharmacokinetics, Safety, and Tolerability of Retosiban in Healthy, Nonpregnant Japanese Subjects.

This study characterized the pharmacokinetics, safety, and tolerability of retosiban in healthy, nonpregnant Japanese women prior to the enrollment of Japanese women in preterm labor in phase 3 trials. This study had 2 cohorts. Cohort 1 was a double-blind, sponsor-open, randomized study in Japanese women. Cohort 2 was an open-label study in white women to compare the pharmacokinetics with those of Japanese women. Retosiban was administered as a 6 mg/h infusion for 24 hours, followed by a 12 mg/h infusion over the next 24 hours; each infusion was preceded by a 6 mg loading dose administered over 5 minutes. Plasma concentrations of retosiban and its major metabolite, GSK2847065, were determined with an informal comparison of pharmacokinetics between Japanese and white women. There was minimal difference in exposure to retosiban or GSK2847065 between Japanese and white women (ratio of 1.03 in retosiban AUC and Cmax ). The 2 doses of retosiban were well tolerated across both populations, and no ethnic difference was observed in the safety profile. Given the results of this study and the known safety profile and dosing flexibility in the phase 3 trials, ethnic-specific dose adjustment of retosiban is not considered necessary for the Japanese and general Asian population.