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Lopinavir concentrations suboptimal at reduced dose of lopinavir/ritonavir 200/50 mg twice daily

Polly Clayden HIV i-Base

An article published online ahead of print in JAIDS, November 2011, shows findings from a pharmacokinetic (PK) study to evaluate a lower dose of lopinavir/ritonavir (LPV/r) than that currently approved.

Reshmie A Ramautarsing and HIV-NAT colleagues from Thailand and the Netherlands performed a two-arm crossover study including 20 HIV-positive Thai patients. Participants receiving a PI-containing regimen (virlogically suppressed <50 copies/mL for at least 4 weeks at enrollment) were randomised receive branded or generic LPV/r dosed at 200/50mg twice daily, in addition to an NRTI backbone.

Due to a compulsory license, Abbott only markets the paediatric formulation (100/25 mg) of LPV/r in Thailand. The Indian generic company, Matrix, has developed a 200/50 mg tablet formulation of LPV/r, which is currently used at the standard dose (400/100 mg twice daily).

Following sampling for PK analysis at week 2, all participants crossed over from their initial study arm to the other. A second sampling was performed at week 4. Participants continued with their study regimen until week 12, when they resumed their pre-study regimen.

There were 10 participants in each arm with a median age, weight and CD4 count of 38.6 (IQR 34.4 – 47.5) years, 59.8 (52.9 – 62.0) kg and 578 (476 – 795) cells/mm3, respectively. The majority (n=17) received standard dose LPV/r and the remainder saquinavir containing regimens prior to the study. None were lost or discontinued their medication during follow up.

The investigators reported comparable bioequivalence for the generic and branded formulations, with point estimates and 90% CI of the geometric mean ratios of 1.00 (0.92-1.09), 1.01(0.90-1.07) and 0.87 (0.76-1.31) for the AUC0-12, Cmax and Ctrough respectively.

Overall 10/40 (25%) samples had subtherapeutic (<1.0 mg/L) plasma concentrations of LPV. These were detected in 8 patients: 2 had subtherapeutic levels measured with both branded and generic formulations, 4 with branded and 2 generic. The lowest concentration was 0.25 mg/L. The investigators noted that all participants reported >90% rates of adherence and 7/8 reported 100% at the time that subtherapeutic plasma concentrations were found.

A comparison of PK parameters for different doses and formulations of LPV/r, using historical data from the same research group, revealed decreased concentrations at lower doses. When compared to LPV/r soft gel capsule (SGC) 400/100 mg twice daily, a dose of LPV/r SGC 266/66 twice daily resulted in 44.1%, 36.0% and 49.1% decreases in LPV concentrations for AUC0-12, Cmax and Ctrough respectively. Using LPV/r generic tablets 200/50mg twice daily decreased the same parameters by 63.5%, 56.6% and 70.2% respectively.

At week 12 all participants remained virologically supressed <50 copies/mL.

The researchers noted that LPV plasma concentrations are dependent on the RTV dose to a greater extent than some other PIs and in this study they had reduced both the LPV and RTV dose, which may explain the subtherapeutic LPV concentrations. They wrote that other dose reduction studies suggest that 200 mg of LPV is sufficient if there is a sufficient boosting dose of RTV (100 mg).

The researchers also noted that this bio-equivalence analysis of LPV/r, although not using the approved 400/100 mg twice-daily dose, demonstrated that the generic and branded tablets result in comparable PK parameters. They wrote: “These data are particularly important for clinicians working in settings where the branded tablets are not available due to compulsory licensing or cost. The availability of safe and effective generic alternatives to branded second line treatment will play an important role in the scaling up of second line treatment in low- and middle-income countries.”

comment

That the generic and originator products are bioequivalent is important.

Previous PK trials have shown that the dose of ritonavir affects LPV levels. In the first dose-ranging trial by Abbott, the dose with the best efficacy and safety profile was 200/100 mg twice daily. If we had 50 mg ritonavir tablets (see below), we could get back to this dose and it may be worth doing more studies.

However, the WHO and Clinton Foundation are more interested in ATV/r and DRV/r, which showed better efficacy and safety profiles than LPV/r (in the CASTLE and ARTEMIS trials, respectively).

Reference:

Ramautarsing RA et al. Neither branded nor generic lopinavir/ritonavir produces adequate lopinavir concentrations at a reduced dose of 200/50mg BID. J Aquir Immune Defic Syndr. Publish ahead of print. DOI: 10.1097/QAI.0b013e3182ba736.

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