Fostemsavir

Fostemsavir is an HIV-1 antiretroviral agent.

Cardiac Electrophysiology

At therapeutic doses, fostemsavir does not prolong the QT interval to any clinically relevant extent. At 4 times the recommended dose, the mean (upper 90% confidence interval) QTcF increase was 11.2 milliseconds (13.3 milliseconds). The observed increase in QTcF was temsavir concentration-dependent.

Exposure-Response Relationship

In the Phase 3 trial evaluating the recommended dosing regimen of fostemsavir (600 mg twice daily) in subjects with multidrug resistant HIV-1 infection on their failing regimen, no relationship was observed between plasma temsavir C_trough and change in plasma HIV-1 RNA from Day 1 to Day 8.

Fostemsavir is a prodrug of temsavir, its active moiety. Fostemsavir was generally not detectable in plasma following oral administration. However, temsavir was readily absorbed (Table 1). Following oral administration, increases in plasma temsavir exposure (C_max and AUC_tau) appeared dose proportional or slightly greater than dose proportional, over the range of 600 mg to 1,800 mg of fostemsavir. The pharmacokinetics of temsavir following administration of fostemsavir are similar between healthy and HIV‑1–infected subjects.

Absorption, Distribution, Metabolism, and Excretion

The pharmacokinetic properties of temsavir following administration of fostemsavir are provided in Table 1. The multiple-dose pharmacokinetic parameters are provided in Table 2.

Table 1. Pharmacokinetic Properties of Temsavir:

HSA = Human Serum Albumin; UGT = Uridine diphosphate glucuronosyl transferases.
^a Dosing in absolute bioavailability study: single-dose administration of fostemsavir extended-release tablet 600 mg followed by single IV infusion of [¹³C] temsavir 100 mcg.
^b Geometric mean ratio (fed/fasted) in pharmacokinetic parameters and (90% confidence interval). Standard meal = ~423 kcal, 36% fat, 47% carbohydrates, and 17% protein. High-calorie/high-fat meal = ~985 kcal, 60% fat, 28% carbohydrates, and 12% protein.
^c Volume of distribution at steady state (Vss) following IV administration.
^d Apparent clearance.
^e In vitro studies have shown that temsavir is biotransformed into 2 predominant circulating inactive metabolites: BMS-646915 (hydrolysis metabolite) and BMS-930644 (N-dealkylated metabolite).
^f Dosing in mass balance study: single-dose administration of [¹⁴C] fostemsavir oral solution 300 mg containing 100 microCi (3.7 MBq) of total radioactivity.

Table 2. Multiple-Dose Pharmacokinetic Parameters of Temsavir:

CV = Coefficient of Variation; C_max = Maximum concentration; AUC = Area under the time concentration curve; C₁₂ = Concentration at 12 hours.
^a Based on population pharmacokinetic analyses in heavily treatment-experienced adult subjects with HIV-1 infection receiving 600 mg of fostemsavir twice daily with or without food in combination with other antiretroviral drugs.

Specific Populations

No clinically significant differences in the pharmacokinetics of temsavir were observed based on age, sex, race/ethnicity (white, black/African American, Asian, or other). The effect of hepatitis B and/or C virus co-infection on the pharmacokinetics of temsavir is unknown.

The pharmacokinetics of temsavir has not been studied in pediatric subjects and data are limited in subjects aged 65 years or older.

Population pharmacokinetic analyses of subjects with HIV-1 infection aged up to 73 years from studies with fostemsavir indicated age had no clinically relevant effect on the pharmacokinetics of temsavir.

Patients with Renal Impairment

No clinically relevant differences in total and unbound temsavir pharmacokinetics were observed in patients with mild to severe renal impairment. No clinically relevant differences in temsavir pharmacokinetics were observed in patients with end-stage renal disease (ESRD) on hemodialysis compared with the same patients with ESRD off hemodialysis. Temsavir was not readily cleared by hemodialysis with approximately 12.3% of the administered dose removed during the 4-hour hemodialysis session.

Patients with Hepatic Impairment

No clinically relevant differences in total and unbound temsavir pharmacokinetics were observed in patients with mild to severe hepatic impairment (Child-Pugh Score A, B, or C).

Drug Interaction Studies

Temsavir is a substrate of CYP3A, esterases, P-glycoprotein (P-gp), and breast cancer resistance protein (BCRP). Drugs that induce or inhibit CYP3A, P-gp, and BCRP may affect temsavir plasma concentrations. Coadministration of fostemsavir with drugs that are strong CYP3A inducers result in decreased concentrations of temsavir. Coadministration of fostemsavir with drugs that are moderate CYP3A inducers and/or strong CYP3A, P-gp and/or BCRP inhibitors are not likely to have a clinically relevant effect on the plasma concentrations of temsavir.

Temsavir is an inhibitor of OATP1B1 and OATP1B3. Additionally, temsavir and 2 metabolites (Table 1) are inhibitors of BCRP. Thus, temsavir is expected to affect the pharmacokinetics of drugs that are substrates of OATP1B1/3 and/or BCRP.

At clinically relevant concentrations, significant interactions are not expected when fostemsavir is coadministered with substrates of CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2E1, 2D6, and 3A4; UGT1A1, 1A4, 1A6, 1A9, 2B7; P-gp; multidrug resistance protein (MRP)2; bile salt export pump (BSEP); sodium taurocholate co-transporting polypeptide (NTCP); multidrug and toxin extrusion protein (MATE)1/2K; organic anion transporters (OAT)1 and OAT3; organic cation transporters (OCT)1 and OCT2 based on in vitro and clinical drug interaction results (Table 3).

Drug interaction studies were performed with fostemsavir and other drugs likely to be coadministered for pharmacokinetic interactions. The effects of temsavir on the pharmacokinetics of coadministered drugs are summarized in Table 3 and the effects of coadministration of other drugs on the pharmacokinetics of temsavir are summarized in Table 4.

Dosing recommendations as a result of established and other potentially significant drug-drug interactions with fostemsavir are provided in Table 3.

Table 3. Effect of Fostemsavir^a on the Pharmacokinetics of Coadministered Drugs:

CI = Confidence Interval; n = Maximum number of subjects with data; NA = Not available.
AUC = AUC_tau for repeat-dose studies and AUC_(0-inf) for single-dose study.
^a Temsavir is the active moiety.

Table 4. Effect of Coadministered Drugs on the Pharmacokinetics of Temsavir^a Following Coadministration with Fostemsavir:

CI = Confidence Interval; n = Maximum number of subjects with data; NA = Not available.
AUC = AUC_tau for repeat-dose studies and AUC_(0-inf) for single-dose study.
C_tau = C₁₂ for single-dose study.
^a Temsavir is the active moiety.