Pharmacokinetics and tolerability of a combination of indinavir, lopinavir and ritonavir in multiply pretreated HIV-1 infected adults.
OBJECTIVE
The authors evaluated the pharmacokinetics and tolerability of indinavir/lopinavir/ritonavir in a protease inhibitor only combination.


METHODS
Plasma drug levels of patients taking indinavir/lopinavir/ritonavir 800/400/100mg twice daily (n = 24, group 1) were compared to patients taking either lopinavir/ritonavir 400/100mg (n = 35, group2) or indinavir/ritonavir 800/100mg (n = 33, group3) twice daily plus nucleos(t)ide reverse transcriptase inhibitors (NRTI). Steady-state drug concentrations were measured by LC/MS/MS. Minimum and maximum concentrations (C subsetmin, C subsetmax), area under the concentration-time curve (AUC subset0-12h), total clearance (CL subsettot) and half-life (t1/2) were calculated. HIV viral load, CD4 cell count and adverse events causing early termination of therapy were correlated over a period of 48 weeks.


RESULTS
Plasma levels of lopinavir/ritonavir were significantly enhanced when combined with indinavir compared to a regimen of lopinavir/ritonavir+NRTI: Mean lopinavir AUC subset(0-12h) 80,912 ng*h/mL vs. 60,548 ng*h/mL; C subsetmin 4,633 ng/mL vs. 3,258 ng/mL; C subsetmax 8,023 ng/mL vs. 6,710 ng/mL. Mean ritonavir AUC(0-12h) 6,907 ng*h/mL vs. 3,467 ng*h/mL; Cmin 220 ng/mL vs. 125 ng/mL; C subsetmax 1,059 ng/mL vs. 522 ng/mL. Indinavir levels were comparable for both indinavir containing regimen. A significantly smaller number of patients stopped indinavir/lopinavir/ritonavir therapy (group1: 16.7%) than indinavir/ritonavir + NRTI treatment (group3: 45.5%) due to adverse events. Virological failure was the main reason for early termination of treatment with indinavir/lopinavir/ ritonavir before week 48 (group1: 50%).


CONCLUSIONS
indinavir/lopinavir/ritonavir 800/400/ 100mg twice daily represents a therapy option with an adequate safety but only short term efficacy for extensively pretreated patients.
von Hentig
Nils
N
Institute for Clinical Pharmacology, J.W.Goethe University Hospital, Frankfurt, Theodor-Stern-Kai 7, D-60590 Frankfurt/M., Germany. Hentig@em.uni-frankfurt.de
Müller
A
A
Rottmann
C
C
Lutz
T
T
Klauke
S
S
Kurowski
M
M
Staszewski
S
S
Harder
S
S
D000328:Adult; D018791:CD4 Lymphocyte Count; D004334:Drug Administration Schedule; D004338:Drug Combinations; D005260:Female; D015658:HIV Infections / Q000276:immunology / Q000378:metabolism*; D017320:HIV Protease Inhibitors / Q000493:pharmacokinetics*; D015497:HIV-1 / Q000378:metabolism*; D006801:Humans; D019469:Indinavir / Q000493:pharmacokinetics*; D061466:Lopinavir; D008297:Male; D013058:Mass Spectrometry; D020714:Maximum Tolerated Dose; D008657:Metabolic Clearance Rate; D011744:Pyrimidinones / Q000493:pharmacokinetics*; D019438:Ritonavir / Q000493:pharmacokinetics*; D019562:Viral Load
D004338:Drug Combinations; D017320:HIV Protease Inhibitors; D011744:Pyrimidinones; D061466:Lopinavir; D019469:Indinavir; D019438:Ritonavir