Multiple-dose pharmacokinetics of ritonavir in human immunodeficiency virus-infected subjects

Abstract

The multiple-dose pharmacokinetics of ritonavir were investigated in four groups of human immunodeficiency virus-positive male subjects (with 16 subjects per group) under nonfasting conditions; a 3:1 ritonavir:placebo ratio was used. Ritonavir was given at 200 (group I), 300 (group II), 400 (group III), or 500 (group IV) mg every 12 h for 2 weeks. The multiple-dose pharmacokinetics of ritonavir were moderately dose dependent, with the clearance for group IV (6.8 +/- 2.7 liters/h) being an average of 32% lower than that for group I (10.0 +/- 3.2 liters/h). First-pass metabolism should be minimal for ritonavir. The functional half-life, estimated from peak and trough concentrations, were similar among the dosage groups, averaging 3.1 and 5.7 h after the morning and evening doses, respectively. The area under the concentration-time curve at 24 h (AUC24) and apparent terminal-phase elimination rate constant remained relatively time invariant, but predose concentrations decreased 30 to 70% over time. Concentration-dependent autoinduction is the most likely mechanism for the time-dependent pharmacokinetics. The Km and initial maximum rate of metabolism (Vmax) values estimated from population pharmacokinetic modeling (nonlinear mixed-effects models) were 3.43 microg/ml and 46.9 mg/h, respectively. The group IV Vmax increased to 68 mg/h after 2 weeks. The maximum concentration of ritonavir in serum (Cmax) and AUC after the evening doses were an average of 30 to 40% lower than the values after the morning doses, while the concentration at 12 h was an average of 32% lower than the predose concentration, probably due to protracted absorption. Less than 2% of the dose was eliminated unchanged in the urine. Triglyceride levels increased from the levels at the baseline, and the levels were correlated with baseline triglyceride levels and AUC, Cmax, or predose concentrations.

Adherence to Anti Retroviral Therapy (ART) During Muslim Ramadan Fasting

“…For instance, in NFT state a reduction of one-third in area under the plasma concentration versus time curve (AUC) was observed after ingestion of the evening dose of ritonovir compared to the morning dose. However, no circadian variations were noted with Lopinavir/ritonovir combination (Hsu et al 1997;Justesen and Pedersen 2002;van Heeswijk et al 2005). Thus, the influence of changes in sleep, waking and circadian variations on ARV pharmacokinetics remains unclear.…”

Ritonavir-Based Highly Active Antiretroviral Therapy in Human Immunodeficiency Virus Type 1-Infected Infants Younger Than 24 Months of Age

“…Ritonavir plasma concentrations were substantially lower and apparent oral clearances were consistently higher than values reported for adults receiving currently recommended dose regimens. 11 For adults receiving 600 mg twice daily, ritonavir apparent oral clearance is 4 -5 liters/h/m 2 , and mean predose concentrations are 3500 -4000 ng/mL. The initial dose of 350 mg/m 2 for cohort 1 is similar to the currently recommended adult dose of 600 mg (ϳ330 mg/m 2 ) twice daily.…”

Position Paper on Therapeutic Drug Monitoring of Antiretroviral Agents

“…Many studies have been published linking antiretroviral exposure to changes in surrogate markers of treatment outcome. [5][6][7][8][9][10][11][12][13][14][15][16][17] It is not within the scope of this paper to review these studies in detail, but rather to summarize collectively their findings and present our best recommendations.…”