Pharmacokinetic Model

Appendix 1

Pharmacokinetic Model

Class 1. Maraviroc- CRAs

Two randomized, placebo-controlled, phase 2a monotherapy studies (A4001007 and A4001015) for maraviroc were combined and mean data were obtained for analysis [9-10]. Clinical PK studies in healthy subjects indicated a non-proportional increase of AUC over 3–1200 mg solution administered orally [17] and dose-related reduction in both maximum concentration (Cmax) and AUC after a high-fat meal [18]. A previously developed PK model was adapted with a two-compartment model (2CM) with first-order absorption, first-order elimination and lag time [10]. A correction factor was introduced on the relative bioavailability in the model to account for the non-proportional increase in exposure across the dose range of 25 – 300 mg under both fed and fasted conditions.

Class 2.Etravirine (TMC125) – NNRTIs

Etravirine plasma concentrations from 32 HIV-infected patients who received 100 mg or 400 mg doses of etravirine from trial C201 and a 900 mg dose of etravirine from trial C208, were available for the PK analysis. Because data were obtained from two different trial sites with two different formulations, a substantial difference between the PK of the two studies was observed. A 2CM assuming a sequential zero-order followed by a first-order absorption process was used to fit the mean concentration-time data [19]. In addition, formulation effects were included on both relative bioavailability and the first order rate constant for absorption, and time-dependent clearance (CL) was used to account for the noted decreased CL with time.

Class 3.TenofovirDisoproxilFumarate–NRTIs

Tenofovir serum concentrations from 16 patients on day 1 and day 14 who received either 1 mg/kg or 3 mg/kg doses were available for the PK analysis [13]. Tenofovir is not a CYP enzyme substrate and is mainly excreted in the urine [12]. Tenofovir clearance exceeds the glomerular filtration rate, indicating active tubular secretion [13]. Following single and multiple doses of tenofovir, a decrease in the clearance was observed in the 3 mg/kg dose group, which may be related to the saturation of renal elimination at the higher dose of tenofovir. For the PK analysis, a 2CM with first-order elimination was previously developed to fit the population oral dosing PK data in HIV-infected patients [20], and the basic structural form of the model remained the same. In order to fit the mean serum concentration-time data after intravenous dosing of tenofovir, time-dependent CL was applied for the high dose group to account for the noted decreased CL with time.

Class 4. GSK1349572 - INSTIs

GSK1349572 plasma mean concentrations from 3 dosing groups of 2 mg, 10 mg and 50 mg were analyzed [15]. Only rich PK profiles at day 10 in HIV-infected patients were available for analysis. GSK1349572 demonstrated low variability and time-invariant PK; steady state was achieved by 7 days of dosing, consistent with the known half-life (~14 h). A one-compartment model assuming first-order absorption and first-order elimination was used to model the day 10 data.