The effects of a nucleoside-sparing antiretroviral regimen on the pharmacokinetics of ritonavir-boosted darunavir in HIV type-1-infected patients.
BACKGROUND
Nucleoside-sparing combination antiretroviral therapy (cART) regimens might be an attractive therapeutic option for HIV type-1 (HIV-1)-infected patients; however, the pharmacokinetic profiles of such regimens are frequently unknown.


METHODS
Fourteen HIV-1-infected patients (age 21-55 years, 64% male) on stable cART with plasma HIV RNA <50 copies/ml entered this Phase I pharmacokinetic study. In period 1, patients received tenofovir/emtricitabine/-darunavir/ritonavir (300/200/800/100 mg) all once daily. During period 2, raltegravir 400 mg twice daily was added to the regimen and in period 3 tenofovir/emtricitabine was discontinued. At steady state, intensive pharmacokinetic sampling was undertaken. Differences in the geometric mean ratio (GMR) for pharmacokinetic parameters between periods 2 versus 1 and period 3 versus 1 were assessed for darunavir and ritonavir (period 3 versus 2 for raltegravir).


RESULTS
No statistically significant differences in pharmacokinetic parameters were observed between period 2 versus period 1. During period 3, darunavir GMR (95% confidence interval) values for trough and maximum plasma concentration (C(trough) and C(max)), area under the plasma concentration-time curve (AUC) and elimination half-life (t(1/2)) were 0.64 ng/ml (0.44-0.93), 1.05 ng/ml (0.90-1.24), 0.92 ng h/ml (0.78-1.08) and 0.69 h (0.46-1.05), respectively, when compared with period 1. No statistically significant changes were observed in ritonavir or raltegravir pharmacokinetic parameters. Darunavir C(trough)<550 ng/ml (the minimum effective concentration for protease-resistant HIV viral isolates) was observed in four patients during period 3 only. No clinically significant safety concerns were reported.


CONCLUSIONS
Darunavir C(trough) is reduced by 36% when administered without tenofovir/emtricitabine in HIV-1-infected patients. This interaction might be of clinical significance in the management of individuals with protease-resistant HIV viral isolates.
Garvey
Lucy
L
Imperial College, Norfolk Place, London, UK. l.garvey@imperial.ac.uk
Latch
Ngaire
N
Erlwein
Otto W
OW
Mackie
Nicola E
NE
Walsh
John
J
Scullard
George
G
McClure
Myra O
MO
Dickinson
Laura
L
Back
David
D
Winston
Alan
A
D000225:Adenine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000627:therapeutic use; D000328:Adult; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000069454:Darunavir; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000627:therapeutic use; D004334:Drug Administration Schedule; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D000068679:Emtricitabine; D005260:Female; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D017320:HIV Protease Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D008297:Male; D008875:Middle Aged; D063065:Organophosphonates / Q000008:administration & dosage / Q000627:therapeutic use; D011760:Pyrrolidinones / Q000008:administration & dosage / Q000627:therapeutic use; D000068898:Raltegravir Potassium; D018894:Reverse Transcriptase Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use; D019438:Ritonavir / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D013449:Sulfonamides / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000068698:Tenofovir; D016896:Treatment Outcome; D055815:Young Adult
D019380:Anti-HIV Agents; D017320:HIV Protease Inhibitors; D063065:Organophosphonates; D011760:Pyrrolidinones; D018894:Reverse Transcriptase Inhibitors; D013449:Sulfonamides; D003841:Deoxycytidine; D000068898:Raltegravir Potassium; D000068698:Tenofovir; D000068679:Emtricitabine; D000225:Adenine; D019438:Ritonavir; D000069454:Darunavir