Effects of oral posaconazole on the pharmacokinetics of atazanavir alone and with ritonavir or with efavirenz in healthy adult volunteers.
BACKGROUND
Patients with HIV/AIDS are at increased risk for opportunistic fungal infections. These patients may require concomitant treatment with antiretrovirals and azole antifungals, and interactions between these classes of drugs should be anticipated.


METHODS
A phase 1, open-label, randomized, crossover, drug interaction study was conducted to assess the pharmacokinetic effects of coadministration of posaconazole (400 mg twice daily), with atazanavir (ATV) (300 mg/d alone) and with ritonavir (100 mg/d) or with efavirenz (400 mg/d) in healthy volunteers.


RESULTS
Posaconazole increased maximum observed plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) of ATV by 2.6-fold and 3.7-fold, respectively. Posaconazole increased ATV Cmax and AUC when administered with ritonavir by 1.5-fold and 2.5-fold, respectively. Most subjects who received ATV (with and without ritonavir) and posaconazole experienced clinically relevant increases in total bilirubin. Coadministration of posaconazole and efavirenz resulted in clinically relevant decreases of posaconazole Cmax and AUC of approximately 45% and 50%, respectively.


CONCLUSIONS
Frequent monitoring of adverse events and toxicity related to antiviral exposure is recommended in the event of coadministration of posaconazole and ATV with or without ritonavir. In addition, because of decreased posaconazole exposure, coadministration with efavirenz should be avoided unless the benefit to patients outweighs the risk.
Krishna
Gopal
G
Early Clinical Research and Experimental Medicine, Schering-Plough Research Institute, 2015 Galloping Hill Rd, Kenilworth, NJ 07033, USA. gopal.krishna@spcorp.com
Moton
A
A
Ma
L
L
Martinho
M
M
Seiberling
M
M
McLeod
J
J
D000284:Administration, Oral; D000328:Adult; D000480:Alkynes; D019380:Anti-HIV Agents / Q000493:pharmacokinetics* / Q000494:pharmacology*; D019540:Area Under Curve; D000069446:Atazanavir Sulfate; D048588:Benzoxazines / Q000008:administration & dosage*; D018592:Cross-Over Studies; D003521:Cyclopropanes; D004347:Drug Interactions; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009842:Oligopeptides / Q000493:pharmacokinetics*; D011725:Pyridines / Q000493:pharmacokinetics*; D019438:Ritonavir / Q000008:administration & dosage*; D014230:Triazoles / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*
D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D003521:Cyclopropanes; D009842:Oligopeptides; D011725:Pyridines; D014230:Triazoles; D000069446:Atazanavir Sulfate; C101425:posaconazole; C098320:efavirenz; D019438:Ritonavir