Pharmacokinetic data with existing antiretrovirals

Jennifer J. Kiser, Courtney V. Fletcher, for

Intracellular concentrations of once- and twice-daily abacavir

Marta Boffito presented data on the plasma and intracellular concentrations of abacavir when given as either 600 mg once daily or 300 mg twice daily. [9]

27 subjects (9 females) completed the study. Plasma exposures of abacavir were similar between patients on 300 mg twice daily and 600 mg once daily, while Cmax was 109% higher and Ctrough 63% lower, as expected, following 600mg once daily vs. 300 mg twice daily. However, intracellular carbovir triphosphate AUC and Cmax were 32% and 99% higher in those on 600 mg once daily.

Plasma concentrations of abacavir were 38% higher in females even after adjusting for weight, and intracellular carbovir triphosphate AUCs were 2-fold higher in females.

Gender effect on intracellular triphosphate concentrations

The finding of a gender effect with regard to intracellular triphosphate concentrations of nucleosides was echoed in a study of tenofovir. [10]

This investigation found no difference in plasma tenofovir concentrations between men and women but did show that women had approximately 50% higher intracellular tenofovir concentrations than did men.

These studies, in conjunction with previous reports showing that women had higher intracellular triphosphate concentrations of zidovudine and lamivudine provide a pharmacokinetic basis to warrant further studies of gender-based differences in nucleoside phosphorylation that incorporate virologic, immunologic and safety evaluations. [11]

Dose reductions of d4T

Stavudine (d4T) is part of generic, fixed dose antiretroviral combination products available in developing countries. However, its use has been associated with toxicities. Thus the pharmacokinetics, efficacy and safety of lower doses of d4T are being explored.

Gilles Peytavin presented data from 57 patients (median weight 72 kg), who had been on a stavudine-containing regimen for a median of 6 years, who decreased their stavudine dose from 40 mg twice daily to 30 mg twice daily. [12]

Eleven of the 57 subjects underwent intensive pharmacokinetic studies while on 40 mg and 30 mg twice daily. Despite d4T AUC and Cmax being reduced by 31% and 44%, respectively, with the dose reduction, 98% and 93% of subjects had viral loads of less than 400 copies/mL at 24 and 48 weeks after d4T dose reduction. Additionally, 6 of 17 patients who reported symptoms of neuropathy on 40 mg reported an improvement at week 48. These data are encouraging for the potential for d4T dose reduction in countries without access to other less-toxic nucleoside analogs.

Effects of different PIs on ritonavir

Ritonavir is frequently used to “boost” the concentrations of other protease inhibitors. However these concomitant protease inhibitors have differing effects on ritonavir concentrations. Higher ritonavir concentrations may lead to rises in lipids and gastrointestinal adverse effects; thus, there may be differences in tolerability between ritonavir-boosted protease inhibitor regimens due to differences in ritonavir concentrations.

Marta Boffito presented data from 16 studies on the effects of eight protease inhibitors on ritonavir concentrations when used as a pharmacokinetic booster. [13]

Overall, atazanavir and indinavir were found to increase ritonavir concentrations by 62 and 72%, saquinavir showed no significant effect, while amprenavir, nelfinavir, darunavir and lopinavir lower ritonavir levels. Tipranavir showed the greatest reduction in ritonavir concentrations by 90% (hence the reason for using a 200 mg dose of ritonavir to boost this agent).

The question posed by these investigators of the differential effects of PIs on ritonavir is interesting and clinically relevant. This initial effort to present a comprehensive examination of the pharmacokinetic effects of protease inhibitors on ritonavir concentrations warrants additional study of these issues.

Food and antacid interactions with tipranavir

Antacids decrease tipranavir exposure by about 25%, thus the potential for an interaction between omeprazole and tipranavir requires investigation.

Charles laPorte and colleagues reported the results of a drug-drug interaction study in 15 healthy volunteers between tipranavir/ritonavir and the proton-pump inhibitor omeprazole. [14]

This study was designed to evaluate the pharmacokinetics of single doses of tipranavir/ritonavir (500/200 mg) given with food alone and after 5 days of omeprazole 40 mg once daily. The geometric mean ratios (and 90% confidence interval) for the tipranavir AUC and Cmax were 1 (0.89, 1.12) and 1.05 (0.94, 1.17), respectively. These data indicate that omeprazole had no adverse affect on tipranavir bioavailability and concomitant therapy with food should be acceptable.

In addition, these authors investigated the effect of food on the pharmacokinetics of tipranavir/ritonavir, 500/200 mg twice daily in healthy volunteers. 32 of 35 participants completed this study. The geometric mean ratios (and 90% confidence interval) for the tipranavir pharmacokinetic characteristics given fasted versus fed were: AUC, 0.99 (0.88, 1.11); Cmax, 1.02 (0.91, 1.14); and Cmin, 1.02 (0.84, 1.23). These data would suggest that tipranavir can be given either with or without food.

However, these data are in contrast to data in the manufacturer’s product information that described an enhanced bioavailability of tipranavir when given with high-fat meals (868 kcal, 53% derived from fat, 31% derived from carbohydrates) with a 31% increase in AUC (1.23-1.39).

The most prudent recommendation until the complete data from this food effect study are available (and perhaps a regulatory agency review) is to continue with the recommendation to administer tipranavir/ritonavir with food.


  1. (PK) study of abacavir (ABC) and its intracellular metabolite carbovir triphosphate (CBV-TP) following 600mg once-daily and 300mg twice-daily administration of ABC in HIV-infected subjects. Abstract 13.
  2. Pruvost et al. A pharmacokinetic study in HIV infected patient under tenofovir disoproxil fumerate (TDF): investigation of systemic and intracellular interaction between TDF and abacavir, or lamivudine, or lopinavir/ritonavir. Abstract 56.
  3. Anderson PL. AIDS 2003: 17:2159-68.
  4. Peytavin G et al. Plasma pharmacokinetic, virological efficacy and safety of a reduced dose of stavudine in HIV-1 infected patients: PHOENIX STUDY. Abstract 33.
  5. Boffito et al. Differences between PI effects on plasma RTV levels: analysis of cross-over PK trials and clinical trials. Abstract 50.
  6. La Porte CJL et al. The effect of omeprazole, food and formulation n the pharmacokinetics of tipranavir coadminitered with ritonavir (RTV). Abstract 59.

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