Objectives: 

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

Methods: 

Peak (C_max) and trough (C_min) 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, 500mg twice a day for 3, 4, and 5 days, respectively, then the full dose of 600mg twice a day. Blood sampling was done in group A within 24h of the occurrence of side-effects and in group B after at least 3 days of the full dosage regimen.

Results: 

Both C_max and C_min were significantly higher (Mann-Whitney U test) in patients with side-effects. C_max 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 C_min 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.