The genotypic inhibitory quotient and the (cumulative) number of mutations predict the response to lopinavir therapy.

For 95 protease inhibitor-experienced HIV-1-infected patients, the genotypic inhibitory quotient (GIQ; trough level/number of mutations) was calculated for lopinavir. Three different sets of mutations showed equal predictive value. However, the use of cumulative numbers of mutations for calculation of the GIQ showed significantly better association with the virological response. Furthermore, the predictive value of the GIQ was no different from that of the number of mutations alone.

Lopinavir/ritonavir reduces lamotrigine plasma concentrations in healthy subjects.

BACKGROUND: Limited data are available about the effect of lopinavir and low-dose ritonavir on glucuronidation. Lamotrigine undergoes glucuronidation. We studied the effect of lopinavir/ritonavir on the pharmacokinetics of lamotrigine and vice versa. METHODS: Twenty-four healthy subjects received 50 mg lamotrigine once daily on days 1 and 2 and 100 mg twice daily on day 3 through day 23. Lopinavir (400 mg twice daily)/ritonavir (100 mg twice daily) was added on day 11. Depending on the decrease in lamotrigine trough level between days 10 and 20, either the study was stopped (<20% decrease) or a dose increase was applied from day 23 to day 31, as follows: increase to 150 mg lamotrigine twice daily if there was a 20% to 33% decrease, increase to 200 mg twice daily if there was a 34% to 66% decrease, and increase to 300 mg twice daily if there was a greater than 66% decrease. On days 10, 20, and 31, 12-hour pharmacokinetic curves were drawn. RESULTS: The mean decrease in lamotrigine trough level between days 10 and 20 was 55.4% (n = 18). A dose increment to 200 mg lamotrigine twice daily was used in all subjects. The area under the plasma concentration-time curve (AUC) values of lamotrigine on day 20 (with lopinavir/ritonavir) and day 10 (without lopinavir/ritonavir) were bioinequivalent, with a point estimate of 0.50 (90% confidence interval, 0.47-0.54). After dose adjustment of lamotrigine to 200 mg twice daily, the AUC on day 31 (n = 15) was bioequivalent to that on day 10, with a point estimate of 0.91 (90% confidence interval, 0.82-1.02). The median AUC ratios of lamotrigine 2N-glucuronide to lamotrigine on day 10 and day 20 were 0.57 (interquartile range, 0.39-0.75) and 1.12 (interquartile range, 0.87-1.31). Pharmacokinetic parameters for lopinavir/ritonavir were similar to historical controls. CONCLUSION: Lopinavir/ritonavir decreases the AUC of lamotrigine, probably by induction of glucuronidation. A dose increment to 200% of the initial lamotrigine dose is needed to achieve concentrations similar to those with lamotrigine alone. Lamotrigine does not appear to affect the pharmacokinetics of lopinavir/ritonavir.

Rhabdomyolysis in an HIV-infected patient with impaired renal function concomitantly treated with rosuvastatin and lopinavir/ritonavir.

The authors describe an HIV-infected patient with moderate renal failure receiving combination antiretroviral therapy. Because of dyslipidaemia he was initially treated with pravastatin but developed rhabdomyolysis after a switch to rosuvastatin. With this case we illustrate that statins as well as antiretroviral therapy are susceptible to clinical relevant drug-drug or drug-disease interactions. Knowledge of these interactions is important to provide patients with the best possible care.

Interaction study of the combined use of paroxetine and fosamprenavir-ritonavir in healthy subjects.

Human immunodeficiency virus-infected patients have an increased risk for depression. Despite the high potential for drug-drug interactions, limited data on the combined use of antidepressants and antiretrovirals are available. Theoretically, ritonavir-boosted protease inhibitors may inhibit CYP2D6-mediated metabolism of paroxetine. We wanted to determine the effect of fosamprenavir-ritonavir on paroxetine pharmacokinetics and vice versa and to evaluate the safety of the combination. Group A started with 20 mg paroxetine every day for 10 days; after a wash-out period of 16 days, subjects received paroxetine (20 mg every day) plus fosamprenavir-ritonavir (700/100 mg twice a day) from days 28 to 37. Group B received the regimens in reverse order. On days 10 and 37, pharmacokinetic curves were recorded. Twenty-six healthy subjects (18 females, 8 males) were included. Median (range) age and weight were 44.4 (18.2 to 64.3) years and 68.8 (51.0 to 89.4) kg. Three subjects were excluded (two because of adverse events; one for nonadherence). Addition of fosamprenavir-ritonavir to paroxetine resulted in a significant decrease in paroxetine exposure: the geometric mean ratios (90% confidence intervals) of paroxetine plus fosamprenavir-ritonavir to paroxetine alone were 0.45 (0.41 to 0.49) for the area under the concentration-time curve from 0 to 24 h (AUC(0-24)), 0.49 (0.45 to 0.53) for the maximum concentration of the drug in plasma (C(max)), and 0.75 (0.71 to 0.80) for the apparent elimination half-life (t(1/2)). The free fraction of paroxetine showed a median (interquartile range) increase of 30% (18 to 42%) after the addition of fosamprenavir-ritonavir. The AUC(0-12), C(max), C(min), and t(1/2) of amprenavir and ritonavir were similar to those of historical controls. No serious adverse events occurred. Fosamprenavir-ritonavir reduced total paroxetine exposure by 55%. This is partly explained by protein displacement of paroxetine. We think that this interaction is clinically relevant and that titration to a higher dose of paroxetine may be necessary to accomplish the needed antidepressant effect.