High variability of plasma drug concentrations in dual protease inhibitor regimens.
Ritonavir (RTV) strongly increases the concentrations of protease inhibitors (PIs) in plasma in patients given a combination of RTV and another PI. This pharmacological interaction is complex and poorly characterized and shows marked inter- and intraindividual variations. In addition, RTV interacts differently with saquinavir (SQV), indinavir (IDV), amprenavir (APV), and lopinavir (LPV). In this retrospective study on 542 human immunodeficiency virus-infected patients, we compared inter- and intraindividual variability of plasma PI concentrations and correlations between the C(min) (minimum concentration of drug in plasma) values for RTV and the coadministered PI C(min) values. Mean RTV C(min)s are significantly lower in patients receiving combinations containing APV or LPV than in combinations with SQV or IDV. With the most common PI dose regimens (600 mg of IDV twice a day [BID], 800 mg of SQV BID, and 400 mg of LPV BID), the interindividual C(min) variability of patients treated with a PI and RTV seemed to be lower with APV and LPV than with IDV and SQV. As regards intraindividual variability, APV also differed from the other PIs, exhibiting lower C(min) variability than with the other combinations. Significant positive correlations between RTV C(min) and boosted PI C(min) were observed with IDV, SQV, and LPV, but not with APV. Individual dose adjustments must take into account the specificity the pharmacological interaction of each RTV/PI combination and the large inter- and intraindividual variability of plasma PI levels to avoid suboptimal plasma drug concentrations which may lead to treatment failure and too high concentrations which may induce toxicity and therefore reduce patient compliance.
Guiard-Schmid
Jean-Baptiste
JB
Department of Clinical Infectious and Tropical Diseases, Tenon Hospital, Paris, France. jean-baptiste.guiard-schmid@tnn.ap-hop-paris.fr
Poirier
Jean-Marie
JM
Meynard
Jean-Luc
JL
Bonnard
Philippe
P
Gbadoe
Ayi Hola
AH
Amiel
Corinne
C
Calligaris
Frédérique
F
Abraham
Bruno
B
Pialoux
Gilles
G
Girard
Pierre-Marie
PM
Jaillon
Patrice
P
Rozenbaum
Willy
W
D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000097:blood* / Q000627:therapeutic use; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D006801:Humans; D012189:Retrospective Studies; D018894:Reverse Transcriptase Inhibitors / Q000008:administration & dosage / Q000097:blood* / Q000627:therapeutic use; D019438:Ritonavir / Q000008:administration & dosage / Q000097:blood* / Q000627:therapeutic use
D019380:Anti-HIV Agents; D018894:Reverse Transcriptase Inhibitors; D019438:Ritonavir