Stanley J. Kolis

Pharmacokinetics of plasma enfuvirtide after subcutaneous administration to patientswith human immunodeficiency virus: Inverse Gaussian density absorption and 2-compartment disposition*

Enfuvirtide (T‐20) is the first of a novel class of human immunodeficiency virus (HIV) drugs that block gp41‐mediated viral fusion to host cells. The objectives of this study were to develop a structural pharmacokinetic model that would adequately characterize the absorption and disposition of enfuvirtide pharmacokinetics after both intravenous and subcutaneous administration and to evaluate the dose proportionality of enfuvirtide pharmacokinetic parameters at a subcutaneous dose higher than that currently used in phase III studies.

Lack of Enzyme‐Inducing Effect of Rifampicin on the Pharmacokinetics of Enfuvirtide

The primary objective was to determine whether rifampicin influences the pharmacokinetics of enfuvirtide in HIV‐1‐infected patients. In a single‐center, open‐label, one‐sequence crossover, clinical pharmacology study, 12 HIV‐1‐infected adults received enfuvirtide (90 mg, twice daily) on days 1 to 3 and days 11 to 13 (morning dose only on days 3 and 13) and rifampicin (600 mg, once daily) from days 4 to 13. Plasma concentrations were measured for enfuvirtide and its metabolite (days 3 and 13) and rifampicin (day 13 only). The ratios of least squares means (LSM) and 90% confidence intervals for enfuvirtide and enfuvirtide metabolite pharmacokinetic parameters (AUC12h, Cmax, Ctrough) were estimated in the presence and absence of rifampicin. Treatments were compared using an analysis of variance for natural log‐transformed variables, with factors patient and treatment. Efficacy and safety were also monitored. Steady‐state rifampicin had no appreciable effect on any of the pharmacokinetic parameters assessed for either enfuvirtide or its metabolite. The ratio of LSM for AUC12h, Cmax, and Ctrough for enfuvirtide was 97.5%, 103%, and 84.9%, respectively, and 108%, 112%, and 92.9%, for the enfuvirtide metabolite. Rifampicin did not affect the t1/2 of enfuvirtide or its metabolite. There were no unexpected effects of rifampicin on the short‐term antiviral effect or safety of the administered antiretroviral treatment. The pharmacokinetics of enfuvirtide are not induced by a 10‐day pretreatment with rifampicin.

Assessment of drug-drug interaction potential of enfuvirtide in human immunodeficiency virus type 1-infected patients

Enfuvirtide is the first drug to block human immunodeficiency virus type 1 (HIV‐1) glycoprotein 41–mediated viral fusion to host cells. This study investigated whether enfuvirtide can influence the activities of cytochrome P450 (CYP) enzymes in HIV‐1–infected patients.

Influence of subcutaneous injection site on the steady-state pharmacokinetics of enfuvirtide (T-20) in HIV-1-infected patients

BACKGROUND Enfuvirtide is the first in a new class of antiretrovirals (ARVs), the fusion inhibitors, and the first ARV to be administered by subcutaneous (s.c.) injection. OBJECTIVES The primary objective of this study was to determine the steady-state pharmacokinetics and relative bioavailability of enfuvirtide following sc injection at three separate anatomical sites: abdomen (A), thigh (B) and arm (C). STUDY DESIGN A single-center, open-label, multiple-dose, three-way randomized, crossover study. Twelve HIV-1-infected adults were recruited from three ongoing Phase II enfuvirtide clinical trials and randomized into three groups. Each group continued to receive s.c. injection of enfuvirtide, at a dose of 90 mg twice daily (bid), according to one of three treatment sequences: ABC, BCA or CAB; over three consecutive periods of approximately 7 days each. Plasma concentrations of enfuvirtide and its metabolite (Ro 50-6343) were measured using a validated liquid chromatography-tandem mass spectrometry method. RESULTS The relative bioavailability of enfuvirtide, based on AUC12h and abdomen as a reference site, was 101% for thigh and 117% for arm. The AUC12h of Ro 50-6343 ranged from 14 to 16% of that for enfuvirtide. Although injection site reactions (ISRs) were common, the overall grading (based on pain or discomfort) of all reported ISRs was Grade 1 (mild). The incidence of ISRs varied according to the site of injection, as did the signs and symptoms associated with them. No patient required treatment for an ISR. CONCLUSIONS Comparability among the three injection sites, in terms of both absorption and the ISR profile, allows HIV-1-infected patients the freedom to choose and to rotate, if necessary, the site of enfuvirtide injection among the three anatomical sites.

Lack of Interaction between Enfuvirtide and Ritonavir or Ritonavir‐Boosted Saquinavir in HIV‐1‐Infected Patients

Enfuvirtide (Fuzeon™) is an HIV fusion inhibitor, the first drug in a new class of antiretrovirals. The HIV protease inhibitors ritonavir and saquinavir both inhibit cytochrome P450 (CYP450) isoenzymes, and low‐dose ritonavir is often used to boost pharmacokinetic exposure to full‐dose protease inhibitors. These two studies were designed to assess whether ritonavir and ritonavir‐boosted saquinavir influence the steady‐state pharmacokinetics of enfuvirtide. Both studies were single‐center, open‐label, one‐sequence crossover clinical pharmacology studies in 12 HIV‐1‐infected patients each. Patients received enfuvirtide (90 mg twice daily [bid], subcutaneous injection) for 7 days and either ritonavir (200 mg bid, ritonavir study, orally) or saquinavir/ritonavir (1000/100 mg bid, saquinavir/ritonavir study, orally) for 4 days on days 4 to 7. Serial blood samples were collected up to 24 hours after the morning dose of enfuvirtide on days 3 and 7. Plasma concentrations for enfuvirtide, enfuvirtide metabolite, saquinavir, and ritonavir were measured using validated liquid chromatography tandem mass spectrometry methods. Efficacy and safety were also monitored. Bioequivalence criteria require the 90% confidence interval (CI) for the least squares means (LSM) of Cmax and AUC12h to be between 80% and 125%. In the present studies, analysis of variance showed that when coadministered with ritonavir, the ratio of LSM for enfuvirtide was 124% for Cmax (90% confidence interval [CI]: 109%‐141%), 122% for AUC12h (90% CI: 108%‐137%), and 114% for Ctrough (90% CI: 102%‐128%). Although the bioequivalence criteria were not met, the increase in enfuvirtide exposure was small (< 25%) and not clinically relevant. When administered with ritonavir‐boosted saquinavir, the ratio of LSM for enfuvirtide was 107% for Cmax (90% CI: 94.3%‐121%) and 114% for AUC12h (90% CI: 105%‐124%), which therefore met bioequivalence criteria, and 126% for Ctrough (90% CI: 117%‐135%). The pharmacokinetics of enfuvirtide are affected to a small extent when coadministered with ritonavir at a dose of 200 mg bid but not when coadministered with a saquinavir‐ritonavir combination (1000/100 mg bid). However, previous clinical studies have shown that such increases in enfuvirtide exposure are not clinically relevant. Thus, no dosage adjustments are warranted when enfuvirtide is coadministered with low‐dose ritonavir or saquinavir boosted with a low dose of ritonavir.

Thorough QT/QTc Study of Ritonavir-Boosted Saquinavir Following Multiple-Dose Administration of Therapeutic and Supratherapeutic Doses in Healthy Participants

The effect of saquinavir‐boosted ritonavir at therapeutic (1000/100 mg twice daily [bid]) and supratherapeutic (1500/100 mg bid) doses was evaluated in a double‐blind, placebo‐ and positive‐controlled (moxifloxacin 400 mg) 4‐way crossover thorough QT/QTc study. Least squares mean estimated study‐specific QTc (QTcS) change from dense predose baseline (ddQTcSdense) was the primary endpoint. Greatest mean increase in ddQTcSdense occurred 12 hours postdose for the 1000/100‐mg group (18.9 ms) and 20 hours for the 1500/10‐mg group (30.2 ms). The upper 1‐sided 95% confidence interval was >20 ms from 2 to 20 hours postdose in both groups. ddQTcBdense and ddQTcFdense were similar to ddQTcSdense. No QTcS, QTcF, or QTcB measurements were >500 ms. One participant receiving 1000/100 mg and 3 receiving 1500/100 mg had a maximum ddQTcSdense >60 ms. More participants with ≥1 adverse event received saquinavir/ritonavir. PubMed search and Roche postmarketing data did not reveal publications or reports directly presenting the effect of saquinavir on QT/QTc or causing torsade de pointes.

Assessment of Metabolic Inhibition Potential of Enfuvirtide Using a 5‐Drug Cocktail in HIV‐1 Infected Patients

Clinical Pharmacology & Therapeutics (2003) 73, P81–P81; doi:

Population Pharmacokinetics of Enfuvirtide in HIV-1-Infected Pediatric Patients Over 48 Weeks of Treatment

The objective of this study was to characterize the population pharmacokinetics of enfuvirtide in HIV‐1‐infected children and adolescents. HIV‐infected patients received combination antiretroviral therapy, including enfuvirtide 2.0 mg/kg subcutaneously, twice daily. Serial and trough blood samples were collected up to 48 weeks. NONMEM was used for population pharmacokinetic analysis. Enfuvirtide exposure was calculated from individual parameter estimates derived from the final model. A total of 218 samples from 43 patients were included in the analysis. Enfuvirtide plasma concentration–time data were described by a 1‐compartment model with first‐order absorption and elimination. The addition of each subjects actual body weight as a covariate affected CL/F but not V/F or Ka. The population CL/F, V/F, and Ka for a 33‐kg reference patient was 1.31 L/h, 2.31 L, and 0.105 h−1, respectively. The final model was CL/F (L/h) = 1.31 · (body weight/33 [kg])0.721. Age did not affect enfuvirtide exposure. These results confirm the appropriateness of body weight–based pediatric enfuvirtide dosing.

Effect of R667, a Novel Emphysema Agent, on the Pharmacokinetics of Midazolam in Healthy Men

The purpose of this study was to investigate the potential for a CYP3A4‐mediated drug interaction between R667 and midazolam (MDZ) in healthy subjects. R667 is metabolized by CYP3A4 and therefore may interact with CYP3A4 substrates. In the present study, 18 healthy male subjects received a single 15‐mg oral dose of MDZ with and without R667 coadministration. Serial blood samples were collected predose and up to 24 hours after each MDZ dose for pharmacokinetic (PK) evaluation. The PK parameters for MDZ, R667, and metabolites were estimated using noncompartmental methods. MDZ exposure was very similar in the presence and absence of R667 (Cmax = 50.8 vs 46.2 ng/mL; AUC0‐last = 215 vs 216 ng•h/mL; AUC0‐last ratio = 0.26 vs 0.26, respectively). R667 exposure was not affected by midazolam coadministration as compared with historical data. Based on the results of this study, no significant pharmacokinetic interaction should be anticipated between R667 and CYP3A4 substrates.

Pharmacokinetics (PK) and pharmacodynamics (PD) of enfuvirtide in hiv‐1 infected adolescents over 24 weeks of treatment

Enfuvirtide (ENF, T‐20, Fuzeon®) is the first of a novel class of HIV drugs which block gp41‐mediated viral fusion to host cells and has been recently approved by both the FDA and European Union. The objective of this study was to evaluate time stability of the pharmacokinetics (PK) of ENF and its metabolite and its antiretroviral activity (PD) in a group of HIV‐1 infected adolescents.