Pharmacokinetic interaction between ritonavir and indinavir in healthy volunteers

Abstract

The pharmacokinetic interaction between indinavir and ritonavir was evaluated in five groups of healthy adult volunteers to explore the potential for twice-daily (b.i.d.) dosing of this combination. All subjects received 800 mg of indinavir every 8 h (q8h) on day 2. In addition, subjects in group I received one dose of 800 mg of indinavir on day 1 and 800 mg of indinavir q8h on day 17. Subjects in Groups II and IV each received one dose of 600 mg of indinavir on days 1 and 17, and subjects in groups III and V each received one dose of 400 mg of indinavir on days 1 and 17. During days 3 to 17, ritonavir placebo or ritonavir at 200, 300, 300, or 400 mg q12h was given to groups I, II, III, IV, and V, respectively. Ritonavir at steady state probably inhibited the cytochrome P-450 3A metabolism of indinavir and substantially increased plasma indinavir concentrations, with the area under the plasma concentration-time curve (AUC) increasing up to 475% and the peak concentration in serum (Cmax) increasing up to 110%. The Cmax/trough concentration ratio decreased from 50 in standard q8h regimens to less than 14 when indinavir was administered with ritonavir. For a constant indinavir dose, an increase in the ritonavir dose yielded similar indinavir AUCs, Cmaxs, and concentrations at 12 h (C12s). For a constant ritonavir dose, an increase in the indinavir dose resulted in approximately proportional increases in the indinavir AUC, less than proportional increases in Cmax, and slightly more than proportional increases in C12. Ritonavir reduced between-subject variability in the indinavir AUC and trough concentrations and did not affect indinavir renal clearance. With the altered pharmacokinetic profile, indinavir likely could be given as a b.i.d. combination regimen with ritonavir. This could potentially improve patient compliance and thereby reduce treatment failures.

FIG. 1

Mean plasma indinavir (IDV) concentration-time profiles after an administration of single dose of 400 mg (groups III and V), 600 mg (groups II and IV), or 800 mg (group I) alone or in combination with ritonavir (RTV) maintained at 200 mg (group II), 300 mg (groups III and IV), or 400 mg (group V) q12h for 2 weeks.

FIG. 2

Relationship between day 17 ritonavir AUC and day 17 indinavir AUC for 400- and 600-mg indinavir doses (subjects in groups II and IV each received 600 mg of indinavir alone or with 200 or 300 mg ritonavir q12h, respectively; subjects in groups III and V each received 400 mg of indinavir alone or with 300 or 400 mg ritonavir q12h, respectively).