Dose optimisation: 50 mg ritonavir-boosting, 3TC dosing and raltegravir once-daily

Courtney Fletcher Pharm.D, University of Nebraska for

The issue of dose optimisation is important for several reasons, ranging from finding the right dose for an individual patient that achieves the highest probability of therapeutic success with the lowest risk of adverse events, to as a strategy to decrease the cost of antiretroviral therapy in order to increase the delivery of therapy to more individuals. A plenary/round table discussion on ‘Dose optimisation and simplification’ focused on the decrease cost to increase access issue.

Here are some compelling reasons to pursue this research: “over 90% of HIV-infected individual live in very poor countries where the cost of antiretroviral treatment can still be a major barrier to access” (Andrew Hill, Liverpool University); “antiretrovirals consume 50% of the drug budget for South Africa…the need to reduce antiretroviral prices is becoming more pressing as ART scale up continues in low- and middle-income countries” (Gary Maartens, University of Cape Town); and “while 5 million individual are currently accessing ARV for treatment, 10 million more require therapy” (Steve Becker, Bill & Melinda Gates Foundation).

Atazanavir drug levels similar with 50 mg or 100 mg ritonavir boosting

Abstract P-31 is a good example of one dose optimisation strategy. This study investigated ATV concentrations in 12 healthy volunteers when given with either 100 mg or 50 mg of RTV for 10 days. [1]

The AUC of ATV when given with 50 mg of RTV was 47.09 mg*h/L and was 50.62 mg*h/L with 100 mg of RTV; the 90% CI of the ratio was 82.5 to 116.38. The ATV trough concentrations were 0.59 mg/L with 50 mg of RTV and 0.79 mg/L with 100 mg; all trough concentrations were above 0.15 mg/L, which is the suggested threshold concentration.

There was also no difference in ATV Cmax with the 2 RTV doses. In the 10-day treatment periods, total and LDL cholesterol significantly increased with the 100 mg RTV dose, whereas there were no significant changes with the 50 mg RTV dose.

These data in HIV-negative volunteers indicate atazanavir exposure was equivalent when given with either 100 mg or 50 mg of RTV, but there were fewer adverse effects on lipid metabolism with the 50 mg RTV dose. These data provide a basis for further studies in HIV-infected persons as a strategy to minimise RTV-associated adverse effects, and as a strategy to decrease the costs of therapy.

3TC dose reduction to 150 mg once-daily fails to achieve sufficient intracellular levels

While the atazanavir/ritonavir example above provides an example of a dose optimisation lead worth pursuing, two other abstracts are examples of strategies that do not.

The first, abstract O-05 evaluated whether a 3TC dose of 150 mg once daily, compared with the usual 300 mg once daily dose, achieved bioequivalent intracellular concentrations of the active metabolite, 3TC-triphosphate. [2]

24 HIV-negative volunteers participated in this study.

The geometric mean 24-hour AUC of 3TC-triphosphate from the 300 mg dose was 59.5 pmol/106 cells; this value for 150 mg was 44.0 pmol/106 cells. The geometric mean 24-hour concentrations were 1.49 pmol/106 cells and 1.23 pmol/106 cells for the 300 mg and 150 mg 3TC doses, respectively.

The geometric mean ratios for AUC and trough concentration were 0.73 and 0.82, respectively, indicating that the 150 mg dose was not bioequivalent to the 300 mg dose.

This was a reasonable study to perform. It was possible the intracellular formation of 3TC-triphosphate might be saturable, and thus lower doses would achieve intracellular concentrations the same as higher doses. This study showed, however, this was not the case. Because bioequivalence was not demonstrated, there is no pharmacologic basis to pursue a lower 3TC dose as a dose optimisation strategy.

Once-daily raltegravir PK

The QDMRK study compared once vs twice daily raltegravir in 770 treatment-naive persons demonstrated once daily therapy was inferior to twice daily, with overall proportions of subjects with HIV-RNA <50cpm at week 48 of 83.2% vs. 88.9%, respectively. PK data were provided at CROI and demonstrated raltegravir trough concentrations with 800 mg once daily were substantially lower than 400 mg twice daily dose.

At the PK Workshop, additional PK data were provided in abstract O-09. [3]

Ctrough values, from the 24-hour intensive PK studies, were lower for once daily RAL: the geometric mean was 40nM for 800mg once daily versus 257nM for 400 mg twice daily. The trough concentration were similarly lower from the spare/population PK data: the geometric mean was 83nM for once daily and was 380nM for twice daily.

Significant relationships were also found between raltegravir concentrations and virologic response. For example, the odds ratio for achieving HIV-RNA below 400 or 50 copies/mL increased with increasing concentrations, and the odds of virologic failure decreased with increasing raltegravir concentrations. From the presentation at the meeting, no clear breakpoint or threshold raltegravir concentrations could clearly be identified.

From the data, it looks that a trough concentration less than approximately 60 nM increases the risk of virologic failure.

These data indicate raltegravir and the investigational integrase inhibitors elvitegravir and dolutegravir all exhibit pharmacodynamic relationships between trough concentrations and virologic response.

This raltegravir study is a clear example of a potential hazard for dose optimisation efforts: for all antiretrovirals, there is some threshold concentration you can’t go below without increasing the risk of virologic failure for a patient.


All references are to the Programme and Abstracts for the 12th International Workshop on Clinical Pharmacology of HIV Therapy, 13-–15 April 2011, Miami.

  1. Estévez J et al. No changes in atazanavir exposure when boosted with 100 mg or 50 mg of ritonavir in health volunteers. Poster abstract P_31.
  2. Else L et al. Pharmacokinetics of plasma lamivudine (3TC), and its active intracellular anabolite 3TC-triphosphate (3TC-TP) over a 24 hour dosing interval following administration of 3TC 300 mg and 150 mg once daily (od) to HIV-negative healthy volunteers. The ENCORE2 Study. Oral abstract O_05.
  3. Wenning L et al. PK/PD analyses for QDMRK, a phase III study of the safety & efficacy of once versus twice-daily raltegravir in treatment-na HIV-infected patients. Oral abstract O_09.

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