The relationship between ritonavir plasma levels and side-effects: implications for therapeutic drug monitoring.

Objectives: To assess whether the neurological or gastrointestinal adverse effects of ritonavir correlate with parameters of ritonavir systemic exposure.

Methods: Peak (Cmax) and trough (Cmin) ritonavir plasma levels were compared in 11 patients experiencing side-effects (group A) versus 10 patients without side-effects (group B). Ritonavir was administered with the following escalation dosing scheme: 300, 400, 500 mg twice a day for 3, 4, and 5 days, respectively, then the full dose of 600 mg twice a day. Blood sampling was done in group A within 24 h of the occurrence of side-effects and in group B after at least 3 days of the full dosage regimen.

Results: Both Cmax and Cmax were significantly higher (Mann-Whitney U test) in patients with side-effects. Cmax was [median (interquartile range)] 26.7 (22.7-33.3) mg/l versus 16.2 (13.4-17.0) mg/l (P = 0.001) and Cmin was 12.6 (9.1-13.9) versus 7.5 (4.9-8.6) mg/l (P = 0.002).

Conclusion: Patients with higher ritonavir concentrations are at a higher risk of experiencing neurological or gastrointestinal side-effects. Individualization of the dosage regimen, e.g. a downward titration of the ritonavir dose in patients with side-effects, guided by plasma level monitoring, may result in a substantial increase in the percentage of patients tolerating ritonavir without increasing the risk of treatment failure as a result of suboptimal systemic exposure.