Coadministration of raltegravir (400 mg twice daily) with atazanavir/ritonavir was studied in healthy volunteers. Raltegravir AUC, Cmax and C12 increased 41%, 24% and 77%, respectively. The mechanism is UGT1A1 inhibition. No dose adjustment required for raltegravir.

Coadministration of atazanavir/ritonavir and raltegravir (400 mg twice daily) increased raltegravir AUC by 41%, Cmax by 24% and Cmin by 77%. Coadministration of atazanavir and raltegravir (1,200 mg single dose) increased raltegravir AUC, C24 and Cmax by 67%, 26% and 16%, respectively. Coadministration of raltegravir 1,200 mg once daily is not recommended. 

Atazanavir did not have a clinically meaningful effect on the pharmacokinetics of 400 mg twice daily raltegravir. No dose adjustment is required when raltegravir 400 mg twice daily or 1200 mg once daily is coadministered. Coadministration of atazanavir (400 mg daily) and raltegravir (100 mg single dose) increased raltegravir Cmax, AUC and Cmin by 53%, 72% and 95% (n=10). Coadministration of atazanavir (400 mg daily) and raltegravir (1200 mg single dose) increased raltegravir Cmax, AUC and Cmin by 16%, 67% and 26% (n=14).

Coadministration of raltegravir (1200 mg, single dose) with atazanavir (400 mg, once daily) was studied in 12 healthy volunteers. Raltegravir AUC, Cmax and C24 increased 27%, 16% and 26%, respectively. The authors hypothesise UGT1A1 inhibition by atazanavir as the mechanism of increased raltegravir exposure. This hypothesis is supported by the observation of elevated bilirubin levels (a UGT1A1 substrate) during atazanavir administration. Atazanavir PK were not studied as raltegravir does not inhibit or induce enzymes involved in atazanavir dispersal.

The pharmacokinetics of atazanavir and raltegravir were investigated in 19 HIV- subjects receiving twice-daily unboosted atazanavir (300 mg twice daily) and raltegravir (400 mg twice daily). Coadministration decreased atazanavir AUC (17%), Cmax (11%) and Cmin (29%). Atazanavir Cmin was 817 ng/ml (GM, range 250-1550 ng/ml) which is well the above the 10-fold protein binding adjusted EC90 for atazanavir against wild-type HIV, and was moderately lower than historical values obtained with atazanavir/ritonavir. When given with atazanavir, the AUC, Cmax and Cmin of raltegravir increased by 54%, 39% and 48%, respectively. The incidence of hyperbilirubinemia was similar after atazanavir (300 mg twice daily) alone or in the presence of raltegravir.

Coadministration of raltegravir (400 mg twice daily) and unboosted atazanavir (300 mg twice daily) was studied in 20 HIV+ subjects. Raltegravir pharmacokinetics were compared to historical data from 24 HIV+ subjects receiving 10-day raltegravir monotherapy.  Atazanavir mean AUC, Cmax and Ctrough were 19237 ng.h/ml, 2879 ng/ml and 799 ng/ml respectively. Raltegravir mean AUC, Cmax and Ctrough were 7649 ng.h/ml, 1732 ng/ml and 506 ng/ml.  Raltegravir trough concentrations were found to be significantly higher in the presence of atazanavir (506 ± 411 vs 177 ± 262 ng/ml).  Patients with atazanavir AUC above the mean or with atazanavir concentrations exceeding the half maximal inhibitory concentration for UGT1A1 had higher raltegravir AUCs compared to patients with lower atazanavir exposure.

The pharmacokinetic interaction between raltegravir (a substrate of UGT1A1) and atazanavir (an inhibitor of UGT1A1) was investigated in HIV- subjects. Coadministration of raltegravir (100 mg single dose) with atazanavir (400 mg once daily for 7 days) increased raltegravir AUC, Cmax and Cmin by 72%, 53% and 95%, respectively. When the recommended dose of raltegravir (400 mg twice daily) was given with atazanavir/ritonavir (300/100 mg once daily), raltegravir AUC, Cmax and Cmin increased by 41%, 24% and 77%, respectively. The authors conclude that the increase in plasma concentrations of raltegravir is not clinically important and does not require dosage adjustment. 

The pharmacokinetics of raltegravir were determined in 19 HIV- subjects following administration of raltegravir alone (400 mg twice daily) or raltegravir/atazanavir (400/400 mg once daily). High inter-individual variability was observed along with significant intra-individual diurnal variation when given twice daily. Despite a significant reduction in raltegravir-glucuronide concentrations, atazanavir did not significantly increase raltegravir concentrations. When given twice daily, geometric mean raltegravir trough concentration, Cmax and AUC were 40 ng/ml, 1016 ng/ml and 3934 ng/ml.h), respectively. When given once daily with atazanavir, raltegravir trough concentration, Cmax and AUC were 1402 ng/ml (37% increase), 13 ng/ml (67% decrease) and 5541 ng/ml.h, respectively. Although atazanavir inhibited the UDP-glucuronosyltransferase-1A1 mediated metabolism of raltegravir, trough concentrations of raltegravir were significantly lower when given once daily with atazanavir than when given twice daily alone.

The pharmacokinetics of raltegravir were determined in 15 HIV+ subjects stable on atazanavir (400 mg once daily) following the addition of raltegravir (800 mg once daily). Values for Ctrough, Cmax and AUC24 were compared to historical values for C12h, Cmax and AUCinf obtained from 20 HIV- subjects receiving a single dose of raltegravir (400 mg). When compared to historical data, coadministration increased raltegravir Cmax by 2.81-fold, increased AUC by 18% and decreased Ctrough by 85% (note, the data were not dose normalised and the comparison for this value is 400 mg C12h vs 800 mg C24h). Raltegravir Ctrough was below target (33 nM) in 4/15 HIV+ subjects. 

Steady state pharmacokinetics of raltegravir and unboosted twice-daily atazanavir were determined in 21 HIV+ subjects receiving atazanavir (200 mg twice daily) and raltegravir (400 mg twice daily). High interindividual variability was observed for both atazanavir and raltegravir. Geometric mean values (95% CI) for atazanavir AUC, Cmax and Ctrough were 6257 ng/ml.h (4334-8172), 1062 ng/ml (676-1448) and 227 ng/ml (122-332), respectively. Values for raltegravir AUC, Cmax and Ctrough were 9085 ng/ml.h (6317-11853), 2402 ng/ml (1496-3308) and 132 ng/ml (1-263), respectively. Five subjects (24%) had atazanavir trough concentrations below the minimum effective concentration of 150 ng/ml. 62% of subjects had viral loads <50 copies/ml at entry, with all subjects reaching undetectable after 2 weeks of therapy.