Effect of saquinavir/ritonavir on P-glycoprotein activity in healthy volunteers using digoxin as a probe.

BACKGROUND: Saquinavir and ritonavir, both human immunodeficiency virus-1 protease inhibitors, also inhibit the adenosine triphosphate-dependent efflux pump P-glycoprotein (P-gp), which is located at a variety of anatomic sites, including the human intestine. P-gp plays an important role in the absorption, distribution and elimination of numerous drugs. This study investigated the inhibitory potential of multiple administrations of ritonavir-boosted saquinavir at the target therapeutic dose of 1,000 mg saquinavir/100 mg ritonavir twice daily on the pharmacokinetics of oral digoxin, a model P-gp substrate that is predominantly excreted as unchanged drug in the urine. METHODS: In an open-label, 1-sequence, 2-period crossover study, a single digoxin dose of 0.5 mg was administered orally on Day 1. From Days 11 through 26, participants received oral administration of saquinavir/ritonavir 1,000/100 mg twice daily. A second dose of digoxin was administered on Day 24. Blood and urine sampling for pharmacokinetic analyses of digoxin was performed at scheduled time points on Days 1 - 4 and Days 24 - 27. Serial blood samples were drawn to determine plasma levels of saquinavir and ritonavir on Days 21 - 24. Adverse event reports were collected. RESULTS: Of the 17 enrolled participants (9 males and 8 females) who received at least one dose of study medication, 16 completed the study. Two weeks of pretreatment with ritonavir and saquinavir resulted in a 1.27-fold increase in digoxin Cmax (90% confidence interval (1.05 - 1.54)) and a 1.49-fold increase in AUC0-72 (90% CI (1.32 - 1.69)). Renal clearance decreased by a factor 0.88 from 111 to 97.3 ml/min while digoxin half-life increased from 37.0 to 45.3 h. The unbound fraction of digoxin was almost unaffected. The changes in digoxin renal clearance and exposure (AUC0-72) following 2 weeks of treatment with saquinavir/ritonavir were found to be more pronounced among female participants compared with males. Plasma concentrations of saquinavir/ritonavir at trough and at 4 h postdose were within the expected ranges for each gender, with female participants showing higher concentrations than male participants. All three treatments were well tolerated, with no serious adverse events noted. Despite the higher digoxin exposure among females compared to males following saquinavir/ritonavir administration, overall safety profiles were similar. On electrocardiographic readings, a trend of a longer PR interval was noted with triple combination of agents. CONCLUSIONS: Pretreatment with saquinavir/ritonavir 1,000/100 mg twice daily increased digoxin exposure most likely via P-gp-inhibition. Given the relatively narrow therapeutic window of digoxin, caution should be exercised when these three drugs are administered together. It is recommended to reduce digoxin doses and to monitor digoxin serum concentrations.

Low penetration of oseltamivir and its carboxylate into cerebrospinal fluid in healthy Japanese and Caucasian volunteers.

Oseltamivir is a potent, well-tolerated antiviral for the treatment and prophylaxis of influenza. Although no relationship with treatment could be demonstrated, recent reports of abnormal behavior in young individuals with influenza who were receiving oseltamivir have generated renewed interest in the central nervous system (CNS) tolerability of oseltamivir. This single-center, open-label study explored the pharmacokinetics of oseltamivir and oseltamivir carboxylate (OC) in the plasma and cerebrospinal fluid (CSF) of healthy adult volunteers over a 24-hour interval to determine the CNS penetration of both these compounds. Four Japanese and four Caucasian males were enrolled in the study. Oseltamivir and OC concentrations in CSF were low (mean of observed maximum concentrations [C(max)], 2.4 ng/ml [oseltamivir] and 19.0 ng/ml [OC]) versus those in plasma (mean C(max), 115 ng/ml [oseltamivir] and 544 ng/ml [OC]), with corresponding C(max) CSF/plasma ratios of 2.1% (oseltamivir) and 3.5% (OC). Overall exposure to oseltamivir and OC in CSF was also comparatively low versus that in plasma (mean area under the concentration-time curve CSF/plasma ratio, 2.4% [oseltamivir] and 2.9% [OC]). No gross differences in the pharmacokinetics of oseltamivir or OC were observed between the Japanese and Caucasian subjects. Oseltamivir was well tolerated. This demonstrates that the CNS penetration of oseltamivir and OC is low in Japanese and Caucasian adults. Emerging data support the idea that oseltamivir and OC have limited potential to induce or exacerbate CNS adverse events in individuals with influenza. A disease- rather than drug-related effect appears likely.

Assessment of the bioequivalence of two nelfinavir tablet formulations under fed and fasted conditions in healthy subjects.

OBJECTIVES: This study was designed to assess the bioequivalence between the commercial 250 mg nelfinavir tablet and the new 625 mg nelfinavir tablet (Roche) which was developed to reduce the daily pill burden for patients from 10 to 4 tablets in a nelfinavir 1250 mg twice daily regimen. METHODS: A total of 52 healthy male subjects were enrolled in this randomized four-period crossover study to receive single oral doses of 1250 mg nelfinavir administered as five commercial 250 mg tablets (reference formulation) and as two new 625 mg tablets (test formulation). Each of the two formulations were taken after an overnight fast and immediately after intake of a standard breakfast (820 kcal) on separate occasions. Blood samples were collected pre-dose and at appropriate intervals after drug administration. Plasma concentrations of nelfinavir and its main metabolite M8 were assayed by a validated LC-MS/ MS assay and the pharmacokinetics of nelfinavir and M8 were derived using standard non-compartmental analysis. RESULTS: The primary parameters for bioequivalence testing were the logarithmically transformed AUC(0-inf) and C(max) of nelfinavir taken from 50 subjects who completed all four treatments. Bioequivalence was accepted if the 90% confidence interval (CI) was contained entirely in the equivalence region (80%, 125%). In the fed state, this criterion was met for AUC (effect ratio = 95%; CI = 87%, 103%) and Cmax (effect ratio = 101%; CI = 94%, 109%) and bioequivalence of the two treatments could be concluded. In the fasted state, AUC clearly failed to meet the bioequivalence criteria (effect ratio = 73%; CI = 59%, 90%) and Cmax was borderline outside the lower acceptance region (effect ratio = 97%; CI = 79.6%, 118%). Therefore, bioequivalence could not be concluded under fasted condition. Food increased the systemic exposure to nelfinavir (as reflected by comparison of the logarithmically transformed AUC(0-inf) values under fed and fasted conditions) by six- and eight-fold after dosing with the 250 mg and the 625 mg tablet, respectively. CONCLUSIONS: Bioequivalence of the new 625 mg nelfinavir tablet relative to the commercial 250 mg tablet, at a dose of 1250 mg, was confirmed in the fed state but not under fasted conditions. As nelfinavir is recommended to be taken with food, the new tablet is well-suited to decrease the daily pill burden for patients on a nelfinavir twice daily regimen and to enhance patient's compliance and adherence.

Limited effect of food composition on the pharmacokinetics of nelfinavir administered twice daily.

UNLABELLED: The objective of the study was to investigate the effect of two different breakfasts on the pharmacokinetics of nelfinavir under steady state conditions. METHODS: Twenty-four healthy male volunteers were evaluated in a 17 days open labeled one sequence crossover study evaluating the effect of a 'light' breakfast (350 kcal) compared to a standard breakfast (800 kcal) on the pharmacokinetics of nelfinavir at steady state during 1250 mg twice daily (BID) administration. RESULTS: After administration with a standard breakfast higher concentrations of nelfinavir were observed during the terminal phase than after administration with a 'light' breakfast. The comparison of the log subset 10 transformed parameters C subset 1-hr-postdose, AUC subset 0-12h, C subset max, and C subset 12 hours, showed that the AUC subset 0-12h was decreased by 13% (P = 0.01) after administration with the 'light' breakfast. Nelfinavir 1250 mg BID was well tolerated. CONCLUSIONS: Although drug intake with a 'light' breakfast' showed a statistically significant decrease for nelfinavir AUC subset 0-12h, this marginal 13% reduction is not considered clinically relevant. No significant effects of the two different breakfasts were found for the remaining three parameters tested C subset 1-hr-postdose, C subset max, and C subset 12 hours.