The breakpoints identified by recursive partitioning for the log viral load changes from baseline at week 2 are summarized in Table 6. Significant breakpoints of vicriviroc C min, C max, and AUC occurred between vicriviroc-treated subjects and placebo. Significant breakpoints of vicriviroc C min, C max, and AUC, separating high from low likelihood of response at week 2, were 53.7 ng/mL, 72.4 ng/mL, and 1460 h ng/mL, respectively. About 70% of subjects achieved a greater than one log viral load decrease when vicriviroc trough concentrations were higher than 53.7 ng/mL, or the AUC was higher than 1460 h ng/mL (Table 6). We assessed the influence of patient characteristics on viral load changes and found no significant impact of race, sex, age, or body weight on vicriviroc efficacy (not shown).
PD Analysis at Weeks 16, 24, and 48
Following the data inclusion criteria, a total of 92 subjects in ACTG study A5211 were used for the PD analysis at week 16, including 26 subjects in the placebo arm and 66 subjects in the vicriviroc-treated arms (Table 5). A total of 84 subjects were used for the PD analysis at week 24, including 25 subjects in the placebo arm and 59 subjects in vicriviroc-treated arm (Table 5). The mean HIV RNA change from baseline was −0.49 log copies/mL and −0.75 log in the placebo arm, vs. −1.98 log copies/mL and −2.05 log copies/mL in vicriviroc arms, at week 16 and 24, respectively (P < 0.05 at both times). No apparent PK-PD relationship could be defined between the log viral load change and vicriviroc exposures (C min, C max, and AUC) at weeks 16 or 24, respectively. Significant breakpoints could be determined between placebo and vicriviroc arms (not shown). However, no statistically significant breakpoints of vicriviroc exposures likely to predict a response were identified within the vicriviroc-treated arms. There was no apparent impact of subjects' race, sex, age, or body weight on viral load change at week 16 or 24 (not shown).
According to the study protocol, vicriviroc dose would be increased for subjects receiving low doses of vicriviroc if protocol-defined virologic failure (less than a one log 10 copies/mL decrease from baseline at/after week 16) was confirmed during the study; in addition, subjects in the placebo arm with confirmed virologic failure could add vicriviroc to their regimen. Under these circumstances, only 52 subjects met the data inclusion criteria for week 48, including 5 subjects in the placebo arm and 47 subjects in vicriviroc treatment arm. Given this small sample size, further PK-PD data analysis was not conducted.
In our study, a 2-compartment model described vicriviroc PK in treatment-experienced HIV infected subjects also taking ritonavir-containing protease inhibitor regimens, when combined with data from healthy HIV-seronegative subjects using population PK modeling. At week 2, higher vicriviroc concentrations were associated with a greater decrease in viral load. However, after subjects received optimized ART regimens, no PK-PD correlation could be defined at weeks 16 and 24. The virologic response to vicriviroc reported here is comparable with that observed by other investigators. Schürmann et al12 observed mean HIV RNA reductions of 1.08, 1.56, and 1.62 log copies/mL at doses of 10 mg, 25 mg, and 50 mg bid (without ritonavir), respectively, in treatment-naive individuals on vicriviroc monotherapy at day 14. Their observed values of mean C max at steady state were 63, 142, and 276 ng/mL, respectively, compared with our results of 33, 69, and 95 ng/mL at vicriviroc doses of 5, 10, and 15 mg QD (with ritonavir), respectively. Landovitz et al15 reported mean HIV RNA reductions of 0.93, 1.18, and 1.34 log10 using vicriviroc doses of 25, 50, and 75 mg once daily, respectively, in treatment-naive subjects on vicriviroc monotherapy (without ritonavir) at day 14.
Data generated from PK-PD studies can reveal important aspects of a drug's behavior, including absorption and elimination kinetics, and identify a range of doses where drug concentrations produce therapeutic and toxic effects. Further, these data can be used to optimize dosing in phase 3 studies where the clinical efficacy of the drug will be most rigorously evaluated. For example, exposure-effect relationships have been explored for abacavir, using population PK data16 and for elvitegravir in a randomized, double-blind placebo-controlled trial.17 Using step-wise additive logistic modeling, McFadyen et al18 identified an average maraviroc concentration of 75 ng/mL as having an 80% probability of producing HIV RNA <50 copies/mL in the Maraviroc vs Efavirenz Regimens as Initial Therapy (MERIT) study of treatment-naive HIV-infected patients. Rosario et al19 developed a comprehensive PK-PD disease model which sought to combine drug effects on viral elimination dynamics from cellular compartments, PK, and virologic response to the CCR5 inhibitor maraviroc. This model was designed to incorporate data from various in vivo and in vitro sources including maraviroc PK in healthy volunteers and maraviroc viral inhibitory constants in vitro. This PK-PD disease model was used to estimate a mean decay rate of actively infected cells expressed as the rate of exponential HIV RNA decline, determined to be −0.58 ± 0.12 day−1 at a dose of 300 mg maraviroc bid.
An important finding of our analysis was the observation that viral load reduction was associated with higher vicriviroc plasma concentrations after 2 weeks of vicriviroc therapy, while remaining on an otherwise failing regimen. Landovitz et al15 found that the reduction in viral load by day 14 correlated with the vicriviroc C min, but that subjects who subsequently failed therapy had a lower mean C min (43.2 vs. 66.2 ng/mL) and AUC (1896.9 vs. 2788.3 ng h/mL). Consistent with these findings, we observed maximum virologic suppression in subjects achieving a steady-state plasma concentration of 56 ng/mL. The vicriviroc 5-mg arm had a substantial number of subjects who were switched from this dose to higher doses due to suboptimal virologic responses and a trend toward emergence of D/M tropism during the study.14
The most likely explanation for the lack of PK-PD correlation at weeks 16 and 24 is the effect of the optimized background regimen started at week 2. The mean change in viral load from baseline to week 2 in the pooled vicriviroc groups was −1.13 log10 copies/mL, whereas the mean change from baseline to weeks 16 and 24 was −1.98 and −2.05 log10 copies/mL, respectively. The additional decrease in HIV RNA comparing weeks 2 with weeks 16 and 24 did not correlate with the assigned dose of vicriviroc. For example, subjects in the 10-mg vicriviroc arm had a greater additional decline in log10 HIV RNA copies/mL than subjects in the highest (15 mg) dose arm at week 16 (10 mg, −1.01 log vs. 15 mg, −0.47 log), and similarly at week 24 (not shown). Moreover, the majority of subjects had sustained plasma concentrations of vicriviroc above 56 ng/mL at weeks 16 and 24, and this concentration was shown by recursive partitioning analysis to be associated with increased likelihood of viral suppression. This concentration is very close to the in vitro IC90 of vicriviroc against wild-type virus, and this finding is consistent with the observation in studies of other antiretroviral agents that optimal pharmacologic response occurs at trough plasma drug concentrations at or above the IC90.17 Valdez et al20 developed a weighted susceptibility score to rank the efficacy of optimized background regimens in treatment experienced patients from the MOTIVATE study who were randomized to maraviroc with optimized background therapy (OBT) or OBT alone. The number of active drugs in the OBT regimen combined with maraviroc was the strongest predictor of virologic suppression at week 48. Collectively, these observations support the importance of the optimized background regimen in the virologic responses seen at weeks 16 and 24. For achieving durable virologic suppression, maintaining plasma concentrations comfortably above of the IC90 may be warranted, particularly in treatment experienced patients. Analysis of larger numbers of treatment-experienced subjects has suggested favorable long-term outcomes in subjects achieving trough concentrations of greater than 100 ng/mL.21
The lack of correlation between PK parameters and virologic response has been observed in a number of HIV treatment scenarios. For example, Mould et al22 observed that virologic response to enfuvirtide was independent of enfuvirtide plasma concentrations, likely because dosing 90-mg bid produced drug concentrations in the plateau portion of the dose response curve. The lack of correlation between plasma vicriviroc concentration and virologic response at weeks 16 and 24 might suggest that all vicriviroc doses produced concentrations in the plateau range of the dose response curve in the presence of an OBT regimen; however, the inferiority of the 5-mg dose makes this explanation unlikely. There is also the possibility that the maximum effect of vicriviroc was not yet achieved by the 2 weeks when the optimal background regimen was initiated, but the inferiority of the 5-mg dosing arm makes this explanation unlikely.
As with maraviroc, the response to vicriviroc is optimal in subjects having only R5 virus detected before initiating treatment.23 Although all subjects in our study had R5-only virus at entry, the first generation tropism assay used in this study is slightly less sensitive in detecting dual/mixed and X4 viruses than the currently available enhanced tropism assay.24 For example, in a reanalysis of the MERIT study, 15% of the subjects with virus classified as R5 (only) before receiving maraviroc were reclassified as having dual/mixed tropism virus by the enhanced tropism assay.25 When these subjects were removed from the analysis, maraviroc demonstrated an effect superior to that observed in the previous analysis of efficacy. Because the predominant quasispecies were R5-only viruses, patients may have an initial virologic response, but subsequently experience virologic failure as the dual/mixed or X4 quasi-species emerge. In our study, a subsequent analysis revealed that 15 out of the 73 subjects designated initially as having R5 virus and randomized to vicriviroc were found to have dual-mixed virus by the enhanced tropism assay.26 These subjects likely experienced a virologic response initially which gradually diminished and may have contributed to the lack of PK-PD correlation at weeks 16 and 24.
Mutations in the env gene that alter HIV-1 gp-120 can confer resistance to maraviroc and vicriviroc.27 Ogert et al28 have identified key determinants for vicriviroc resistance in the C2-V5 domain of gp-120. Acquisition of these mutations during the vicriviroc “monotherapy” phase might have altered the association between PK and PD at later points in the study. Initially, vicriviroc-resistant virus was only identified in one subject in this study (a subject with clade C HIV29), but 3 other cases of resistance were subsequently detected. Because the target of vicriviroc is a host receptor, the ability of chemokine receptor antagonists to modulate the expression of these receptors should be considered as a factor that may affect drug exposure-response relationships, although long-term downregulation of receptor expression has not been reported.
Structurally diverse small-molecule CCR5 antagonists all seem to bind to the same site within the transmembrane domain of CCR5.30 In clinical studies with vicriviroc as short-course monotherapy (14 days), suppression of viral load persisted 2-3 days beyond the end of treatment,12 an effect observed with other CCR5 antagonists.31 In some studies, viral load continued to decrease after discontinuation of the drug, suggesting prolonged CCR5 receptor occupancy. Although the unique effects of these drugs at the receptor could confound the interpretation of PK-PD relationships at 16 and 24 weeks, this is unlikely the case here because such a relationship was observed at week 2.
Consideration of potential PK interactions with other antiretrovirals is important in assessing vicriviroc PK and PD. Metabolic pathways for vicriviroc include N-oxidation, O-demethylation, N,N-dealkylation, N-dealkylation, and oxidation to a carboxylic acid. Cytochrome P450 3A4 catalyzed production of all these metabolites, whereas CYP3A5 and CYP2C9 produced restricted sets of these metabolites.32 When dosed at 10 mg QD, vicriviroc exposure is increased to a similar extent by ritonavir at any dose equal to or greater than 100 mg.33 Coadministration of vicriviroc (15 mg QD) with ritonavir-boosted protease inhibitors produced no significant changes in any vicriviroc PK parameters compared to vicriviroc dosed with 100 mg of ritonavir QD or bid.34 Efavirenz can induce vicriviroc metabolism resulting in significant reductions in vicriviroc AUC and C max when dosed at 10 mg; however, the addition of ritonavir 100 mg attenuates this interaction.33The findings from our study can be informative in the selection of doses and the design of phase 3 studies with vicriviroc in treatment-experienced subjects also taking ritonavir. Matthias et al,35 demonstrated that doses of 100 mg of ritonavir can produce maximal “boosting” of plasma concentrations of different CYP3A substrates, including the HIV integrase inhibitor elvitegravir. A dose of 10 mg vicriviroc with 100 mg of ritonavir produced an average C min (91 ng/mL) which is higher than the steady-state plasma concentration we found to be associated with 90% maximal viral suppression (56 ng/mL). The virologic response we observed at this dose of vicriviroc is comparable with the response observed in studies of treatment-naive subjects using unboosted vicriviroc at higher doses.12,15 On the other hand, a dose of 15 mg vicriviroc with ritonavir 100 mg QD produced a higher C min, C max, and AUC than the 10-mg dose, but no improvement in virologic response at week 2. Long-term virologic suppression was confirmed in treatment-experienced patients receiving 20 mg (QD) or 30 mg (QD) vicriviroc with ritonavir-boosted protease inhibitor-containing regimen in a phase 2b study.36 The PK-PD findings from our analysis, combined with the data identifying the dose producing the most durable suppression in treatment-experienced patients, led to the selection of the 30-mg dose for phase 3 studies.
We have shown a relationship between the PK of vicriviroc in treatment-experienced subjects and the magnitude of short-term virologic benefit. Our results highlight the importance of optimizing the other antiretrovirals in a combination regimen to achieve durable suppression with vicriviroc. Utilization of enhanced tropism assays and genotypic and phenotypic resistance testing to select an optimized background regimen are important adjuncts to maximizing benefit from this class of drugs.
The authors would like to thank the following individuals and organizations for their contributions to this work: all members of the A5211 team and all participating ACTG sites, the A5211 study subjects, and Schering-Plough Research Institute.
Supported by the National Institutes of Allergy and Infectious Diseases, ACTG grant number AI-68636, ACTG SDMC grant number AI68634, ACTG grants AI-51966 (K24 to R.M.G.), AI-69419 (Cornell CTU), and AI-69465.
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Keywords:© 2010 Lippincott Williams & Wilkins, Inc.
HIV; vicriviroc; pharmacokinetics/pharmacodynamics; CCR5 antagonists