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.