Assessment of drug-drug interaction potential of enfuvirtide in human immunodeficiency virus type 1-infected patients.
BACKGROUND
Enfuvirtide is the first drug to block human immunodeficiency virus type 1 (HIV-1) glycoprotein 41-mediated viral fusion to host cells. This study investigated whether enfuvirtide can influence the activities of cytochrome P450 (CYP) enzymes in HIV-1-infected patients.


METHODS
An open-label, 1-sequence crossover study was conducted in 12 HIV-1-infected adults, by use of a 5-drug cocktail consisting of caffeine, chlorzoxazone, dapsone, debrisoquin (INN, debrisoquine), and mephenytoin to assess the activities of CYP1A2, CYP2E1, CYP3A4, CYP2D6, and CYP2C19, respectively. Dapsone was used to assess N-acetyltransferase activity. Patients received a single dose of the cocktail alone on day -15 and another together with enfuvirtide on day 6. Enfuvirtide (90 mg subcutaneously) was administered twice daily on days 1 to 7. Phenotypic index parameters were estimated and analyzed by ANOVA with factors subject and day (-15 and 6).


RESULTS
The phenotypic index parameters, with and without enfuvirtide, for CYP3A4 (0.33 versus 0.34; 90% confidence interval [CI] for ratio of least squares means, 0.88-1.09), CYP2D6 (0.72 versus 0.71; 90% CI, 0.97-1.06), and N-acetyltransferase (0.35 versus 0.39; 90% CI, 0.82-0.98) were bioequivalent. The phenotypic index parameters, with and without enfuvirtide, for CYP1A2 (0.76 versus 0.81; 90% CI, 0.71-1.17), CYP2E1 (1.3 versus 1.2; 90% CI, 0.87-1.29), and CYP2C19 (93 versus 81.8; 90% CI, 0.98-1.28) were not bioequivalent but were not substantially different.


CONCLUSIONS
Enfuvirtide had no clinically important effect on the metabolism of probe drugs mediated by CYP3A4, CYP2D6, or N-acetyltransferase and had little effect on the metabolism of drugs mediated by CYP1A2, CYP2E1, or CYP2C19. The potential for interactions between enfuvirtide and concomitantly administered drugs metabolized by the CYP enzymes tested in this study is low.
Zhang
Xiaoping
X
Department of Clinical Pharmacology, Roche, Nutley, NJ 07110, USA. xiaoping.zhang@roche.com
Lalezari
Jacob P
JP
Badley
Andrew D
AD
Dorr
Albert
A
Kolis
Stanley J
SJ
Kinchelow
Tosca
T
Patel
Indravadan H
IH
D000328:Adult; D000368:Aged; D000704:Analysis of Variance; D016001:Confidence Intervals; D018592:Cross-Over Studies; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D004347:Drug Interactions / Q000502:physiology; D000077560:Enfuvirtide; D005260:Female; D015700:HIV Envelope Protein gp41 / Q000378:metabolism* / Q000627:therapeutic use; D015658:HIV Infections / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D008297:Male; D008875:Middle Aged; D010446:Peptide Fragments / Q000378:metabolism* / Q000627:therapeutic use; D010641:Phenotype
D015700:HIV Envelope Protein gp41; D010446:Peptide Fragments; D000077560:Enfuvirtide; D003577:Cytochrome P-450 Enzyme System