Delavirdine increases drug exposure of ritonavir-boosted protease inhibitors

The co-administration of low doses of ritonavir, a potent cytochrome p450 3A4 inhibitor, has been exploited as a strategy to enhance drug exposure to protease inhibitors, including saquinavir, indinavir, amprenavir, and lopinavir [1–4]. This strategy may lead to decreased pill burden, increased adherence, and reduced cost [5,6]. More recently, it has become apparent that low and intermediate levels of HIV-1 resistance to protease inhibitors may be overcome by increased exposure to these agents, which can be readily achieved with ritonavir boosting. Once patients show evidence of virus with higher levels of resistance to multiple drug classes, regimens including two or more protease inhibitors are often used. In such cases, low-dose ritonavir may be used to boost exposure to two or more protease inhibitors simultaneously (so-called dual boosting). The non-nucleoside reverse transcriptase inhibitors nevirapine and efavirenz are commonly used in multiple drug rescue therapy regimens. Both are cytochrome p450 3A4 inducers, and can thereby decrease exposure to protease inhibitors by 24–62% [7,8]. In contrast, delavirdine is a cytochrome p450 3A4 inhibitor, which has been shown to enhance exposure to indinavir, saquinavir, ritonavir, and nelfinavir [9,10]. The pharmacokinetic impact of delavirdine in dual boosted protease inhibitor-containing regimens has not previously been described. We describe here the pharmacokinetic impact of delavirdine on protease inhibitor levels among three patients receiving multiple drug rescue therapy regimens including dual boosted protease inhibitors. Plasma drug levels were measured before and again at least 2 weeks after the addition of delavirdine. Blood samples were drawn immediately before and every 2 h for 12 h after a timed, observed medication dose. Plasma was separated within 1 h and stored at −70°C until analysis. Plasma drug concentrations were determined by a validated assay using high performance liquid chromatography coupled with tandem mass spectrometry. Lower limits of quantitation were 277 ng/ml for lopinavir, 55 ng/ml for amprenavir, 46 ng/ml for saquinavir, and 92 ng/ml for ritonavir. All three patients received lopinavir 533 mg/ritonavir 133 mg twice a day and amprenavir 750 mg twice a day. Patient 2 also received saquinavir soft gel capsules 800 mg twice a day. Patient 1 was receiving indinavir 600 mg twice a day and nevirapine 200 mg twice a day, which were discontinued when delavirdine 600 mg twice a day was added. The other two patients (nos. 2 and 3) replaced efavirenz 600 mg a day with delavirdine 600 mg twice a day, but made no other changes to their regimens. All three patients were receiving didanosine and lamivudine; patient 1 also received abacavir, patient 2 abacavir and stavudine, and patient 3 received zidovudine. Nucleosides were constant for each individual before and after the switch to delavirdine. Changes in protease inhibitor pharmacokinetic parameters after versus before the addition of delavirdine are summarized in Table 1. After the change to delavirdine, amprenavir area under the curve (AUC)(0−−12) increased by 12 to 105%, Cmin increased by 33 to 71% and Cmax increased by 8 to 107%. Lopinavir AUC(0−−12) increased by 8 to 134%, Cmin increased by 13 to 818% and Cmax changed by −18 to 104%. Ritonavir AUC(0−−12) changed by −33 to 208%, Cmin increased by 0 to > 82% and Cmax changed by −14 to 167%. In the single patient also taking saquinavir, the AUC(0−−12) increased by 78%, the Cmin by 182%, and the Cmax by 28%. The change to delavirdine was not associated with clinical or laboratory toxicities in any of these patients.Table 1: Changes in pharmacokinetic parameters after the addition of delavirdine. These results demonstrate the impact of changing from an alternative non-nucleoside reverse transcriptase inhibitor to delavirdine on protease inhibitor levels among patients receiving multiple drug rescue therapy regimens including dual boosted protease inhibitors. In all three cases, changing to delavirdine was well tolerated and was associated with a variably increased exposure to the protease inhibitors in these ritonavir-boosted combinations. Further evaluation of the clinical role of delavirdine in dual boosted protease inhibitor-containing regimens seems warranted on the basis of these data. In addition, our results illustrate the potential insights that can be gained using therapeutic drug monitoring in the clinical setting. Marianne Harris Chris Alexander Michael O'Shaughnessy Julio S. G. Montaner

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