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

Gatti, Giorgioa; Di Biagio, Antonioa; Casazza, Rosettaa; De Pascalis, Cletaa; Bassetti, Matteoa; Cruciani, Mariob; Vella, Stefanoc; Bassetti, Dantea

Clinical: Original Papers

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, 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 Cmax and Cmin 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.

From the aDepartment of Infectious Diseases, University of Genoa, Genoa, Italy; bDepartment of Infectious Diseases, University of Verona, Verona, Italy; and cVirology Laboratory, Istituto Superiore di Sanita, Rome, Italy.

Sponsorship: This work was supported by the Istituto Superiore di Sanita (ISS) grant no. 30A.0.07.

Corespondence to: Giorgio Gatti, PhD, Clinica di Malattie Infettive-Pad 9 F, Ospedale San Martino, Largo R. Benzi 10, 16132 Genova, Italy. Tel: +39-010-353 7677; fax: +39-010-353 7680; e-mail: gigatti@smartino.ge.it

Received: 19 January 1999; revised: 3 June 1999; accepted: 10 June 1999.

© 1999 Lippincott Williams & Wilkins, Inc.