Pharmacology of investigational drugs

Jennifer J. Kiser, Courtney V. Fletcher, for

Maraviroc and darunavir/r

Maraviroc is a CYP3A4 and P-glycoprotein substrate, thus previous interaction studies have shown that a lower dose of maraviroc, 150 mg twice daily, should be used in combination with protease inhibitors (excluding tipranavir/ritonavir).

John Davis presented data on the interaction between maraviroc 150 mg twice daily and darunavir/ritonavir in 12 healthy volunteers. [24]

Maraviroc AUC and Cmax were increased 405% and 229%, respectively when combined with darunavir/ritonavir. This increase is consistent with other protease inhibitors and thus, the reduced 150 mg twice daily dose is recommended in combination with darunavir/ritonavir.

In this study, as has been the case with all maraviroc drug interaction studies, maraviroc is administered in the fasting state, approximately 1.5 hour prior to the dosing of the protease inhibitor in combination with food. Food decreases maraviroc concentrations by about 50%, however there are no data on the magnitude of these drug interactions when administered with food.

As more concentration-response data with this agent become available, it will be important to determine if the maraviroc concentrations achieved when taken in combination with other protease inhibitors and food fall within the therapeutic range for this drug. If so, that would eliminate the food incongruence between this agent and many other antiretroviral compounds.


Vicriviroc is an investigational CCR5 inhibitor. Charles Flexner presented data exploring the relationship between vicriviroc concentrations and antiretroviral effects. [25]

Two concentrations were obtained from 86 treatment experienced patients participating in a Phase II clinical trial of vicriviroc at doses of 5, 10, or 15 mg once daily in combination with ritonavir-boosted protease inhibitor regimens (Adult AIDS Clinical Trials Group study 5211). In this study, patients randomized to vicriviroc received the drug with their current failing antiretroviral regimens for two weeks, then patients continued on vicriviroc but their background regimen was optimized based on resistance test results.

The concentration data from these 86 patients were combined with intensive pharmacokinetic data from 110 healthy volunteers from five Phase I vicriviroc studies to develop a pharmacokinetic/pharmacodynamic model. At week 2, a Cmin above 54 ng/mL (the EC90 for this drug is 56 ng/mL) and an AUC above 1460 ng*hr/mL were associated with greater viral load decreases. This relationship was no longer apparent at weeks 16 or 24, most likely because treatment response at that point also depended on having other active drugs in the regimen.

Data were presented on the combination of vicriviroc and tipranavir/ritonavir in 8 healthy volunteers. [26]

Volunteers received vicriviroc 15 mg once daily plus ritonavir 200 mg twice daily for two weeks. Tipranavir 500 mg twice daily was then added for an additional two weeks. Vicriviroc AUC and Cmax were reduced 6% and 12%, respectively when combined with tipranavir/ritonavir, thus consistent with other ritonavir-boosted protease inhibitors, no vicriviroc dose adjustment is necessary.


Tipranavir/ritonavir reduces the concentrations of many nucleoside analogs. However, the AUC and Cmax of apricitabine, an investigational nucleoside analogue, are actually moderately increased by 40 and 25%, respectively by tipranavir/ritonavir. [27]

Adverse effects with the combination were mainly nausea, anorexia, headache, and elevated liver enzymes, which are consistent with the side effect profile of tipranavir/ritonavir. Additional studies of the safety of this combination and data on the intracellular concentrations of apricitabine (the active moiety of the nucleoside analogs) in combination with tipranavir/ritonavir are needed.

The pharmacophore of the HIV integrase inhibitors forms a complex with divalent cations (magnesium) at the active site of the integrase enzyme. This propensity for cation binding can result in an interaction with antacids at the level of drug absorption upon co-administration due to the high concentrations of di- and tri-valent cations in antacids.

Antacids and elvitegravir

Thus the effect of simultaneous and staggered administration of antacids and elvitegravir (GileadÂ’s investigational integrase inhibitor, also known as GS-9137) were presented. [28]

The effect of omeprazole 40 mg on elvitegravir absorption was also evaluated. The dose of elvitegravir used in this study was 50 mg with a 100 mg boosting dose of ritonavir administered once daily. Omeprazole did not alter elvitegravir absorption, thus this compound does not exhibit pH-dependent absorption. However, as expected, simultaneous administration of antacid reduced elvitegravir concentrations by about 50%. Separating the antacid by 2 hours only decreased elvitegravir concentrations by 10-20%, however elvitegravir concentrations were unchanged if separated by 4 hours.

Source: Further coverage of the workshop is provided in additional reports posted to the NATAP website.


  1. Abel S et al. An open, randomized, 2-way crossover study to investigate the effecvt og darunavir/ritonavir on the pharmacokinetics of maraviroc in healthy subjects. Abstract 55.
  2. Flexner C et al. Pharmacokinetic/pharmacodynamic modeling of the antiretroviral activity of the CCR5 antagonist vicriviroc in treatment-experienced HIV-infected patients (ACTG 5211). Abstract 15.
  3. Sansone-Parsons A et al. The addition of tipranavir has no impact on the pharmacokinetics of vicriviroc when coadministered with a potents CYP3A4 inhibitor such as ritonavir. Abstract 57.
  4. Moore SM et al. Comparison of the pharmacokinetics of apricitabine in the presence and absence of ritonavir booster tipranavir. Abstract 68.
  5. Ramanathan S et al. Pharmacokinetic evaluation of drug interactions with ritonavir-boosted HIV integrase inhibitor GS-9137 (elvitigravir) and acid-reducing agents. Abstract 69.

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