This study presents the first population pharmacokinetic analysis of RAL in both HIV+
individuals and healthy volunteers. The results show that RAL has a high apparent clearance and is widely distributed, with values for clearance, volume of distribution, and half-life comparable with published data (7
). The high apparent clearance suggests that RAL is a high-extraction drug, subject to significant first-pass metabolism. It was therefore assumed that differences in the kinetics between HIV+
individuals would depend mainly on variations in oral bioavailability. As expected, a very large interindividual variability on RAL bioavailability was observed. The 25% lower relative bioavailability in HIV+
individuals than in healthy volunteers might be related to adherence issues, since HIV−
individuals were studied under more standardized conditions of drug intake and food status. We cannot, however, exclude the possibility that this difference is related to the HIV disease, as gastrointestinal or malabsorption problems have been reported in HIV+
). The RAL absorption half-life was very variable, which is consistent with previously reported data (2
). The slower absorption half-life of RAL in HIV+
individuals could be attributed to HIV-related motor gastrointestinal abnormalities or delayed gastric emptying, but it seems to have a modest impact on time to peak (data not shown) (23
). It might also be the consequence of a difference in food intake between the study populations, since meal type has been shown to explain part of the variability in RAL absorption (6
). The important variability observed in the absorption profile in both HIV+
and healthy subjects under standardized feeding condition indicates, however, that factors other than food intake state might be involved. The lack of information on factors with a potential effect on RAL absorption limits the interpretation of the results.
In line with previously reported data (10
), we observed an approximately 40% increase in RAL bioavailability induced by ATV coadministration, as a consequence of ATV-mediated UGT1A1 inhibition (10
). The small and nonsignificant 20% decrease in RAL bioavailability induced by EFV is similar to previous observations (19
). The lack of statistical significance is probably due to both the limited number of patients (n
= 14) exposed to the association and the modest influence of EFV. RAL is commonly used with tenofovir, which has been shown to modestly increase RAL exposure (47
), and with etravirine, which is known to induce UGT1A1, resulting in a slight decrease in RAL concentrations (1
). However, no significant effects were found in this study for either drug.
In contrast to other reports (20
), we found a 65% higher RAL exposure in female than in male patients. Sex-related pharmacokinetic disparities have been reported for other antiretroviral drugs (34
). There are many potential reasons for gender differences in RAL pharmacokinetics, such as differences in gastric pH, which is higher in females (36
), lower hepatic expression of ABCB1 P-glycoprotein in females (31
), and lower hepatic blood flow and consequently lower hepatic metabolic capacity (31
), which could partly explain our findings. We observed a 60% lower volume of distribution in Caucasian patients compared to patients of other ethnicities, who were mostly black patients. Ethnic differences in drug distribution have been reported with many drugs, which were attributed mainly to differences in protein binding and in particular in binding to alpha1-acid glycoproteins (AAG) (orosmucoid) (21
). RAL, formulated as a potassium salt (27
), might preferentially bind to AAG, although this has not been formally demonstrated. An ethnicity-based difference in AAG levels could thus explain the difference in the distribution of RAL (21
). The clinical significance of this finding is still not clear and needs more investigation with larger patient cohorts.
A clear relationship between RAL exposure and treatment outcome has not been formally reported (35
). However, some recent evidence suggests a possible role of drug concentration, in addition to virological parameters, in the efficacy and induction of virological resistance to RAL (12
). In accordance with results of the QD Merck study (35
), our simulations of 400 mg BID compared to 800 mg QD indicate that a higher percentage of patients would exhibit Cmin
under the protein-adjusted IC95
with the 800-mg QD regimen than with 400 mg BID, which might put patients at risk of virological failure, in particular those with a high viral load, as reported by Eron et al. (14
). Considering the very large BSV variability encountered, some patients might also exhibit very low RAL concentrations with the standard 400-mg BID regimen, which suggests that therapeutic drug monitoring of this drug could be relevant in some situations. However, the rather high intrapatient variability might limit its effectiveness. Based on some evidence about pharmacokinetic and pharmacodynamic relationships (12
) and on the good correlation between RAL intracellular concentrations and plasma concentrations (16
), there is a need to further explore the relationship between efficacy and pharmacokinetic exposure and the potential role of concentration monitoring. Better-standardized studies based upon more extensive sampling on a better-defined population would circumvent some of the limitations inherent to observational studies.
Genetic variations in UGT isoenzymes and nuclear receptors were not significantly associated with RAL exposure, except for the UGT1A9
, which needs further confirmation. UGT1A9
is a loss-of-function allele that is substrate specific. It has been associated with decreased glucuronidation activity of irinotecan and mycophenolic acid but not flavopiridol (4
). Studies using RAL metabolite profiles as the phenotype may represent a better alternative to identify genetic variants influencing RAL exposure.
In conclusion, the RAL pharmacokinetic profile is characterized by high interpatient and residual variability. ATV, gender, and hyperbilirubinemia appear to affect RAL bioavailability, whereas ethnicity affects the volume of distribution. Except possibly for UGT1A9*3, no genetic polymorphisms was found to explain the large RAL pharmacokinetic variability. Owing to this very large variability, drug concentrations may be very low under the standard dosage regimen of 400 mg BID and further decreased with 800 mg QD, suggesting that therapeutic drug monitoring of RAL could yet be relevant in some situations. Further studies focusing on concentration-response relationships should be performed to better define target plasma concentrations.