Therapeutic Drug Monitoring (TDM) Reveals Lower Levels of Lopinavir/Ritonavir When Given with Efavirenz or Nevirapine

The aim of the current study was to evaluate the inter-individual variability in the plasma concentrations of [the HIV protease inhibitor] lopinavir [Kaletra] in the context of routine monitoring with or without treatment with a non-nucleoside reverse transcriptase inhibitor (NNRTI) and to assess the interaction between the co-formulation of lopinavir/ritonavir and efavirenz [Sustiva] or nevirapine [Viramune].

Plasma trough and peak concentrations (C(trough), C(max)) of lopinavir from 182 HIV-1-infected patients were analyzed by high-performance liquid chromatography. Three lopinavir/ritonavir regimens were assessed, namely

(A)    400 mg lopinavir/100 mg ritonavir twice daily given alone (n = 125);

(B)    400/100 mg twice daily together with a non-nucleoside reverse transcriptase inhibitor (n = 25); and

(C)    533/133 mg twice daily together with a non-nucleoside reverse transcriptase inhibitor (n = 32).

Results

Median (ng ml(-1)) C(trough) and C(max) lopinavir (interquartile range, CV) were:

(A)    4852 (3198-6891, 56%) and 8501 (6333-11 584, 41%),

(B)    2979 (1704-5186, 74%) and 5612 (3362-11 704, 76%) and

(C)    5082 (2696-7226, 74%) and 9757 (4883-12 963, 60%).

Median C(trough) of lopinavir was lower in patients taking both efavirenz (P = 0.01] and nevirapine (P = 0.019) compared with those taking lopinavir/ritonavir alone.

A higher inter-individual variability was observed when lopinavir/ritonavir was given with a non-nucleoside reverse transcriptase inhibitor. The risk of achieving a 'suboptimal'C(trough) of lopinavir (below a threshold of 3000 ng ml(-1)) was statistically higher in patients treated with a non-nucleoside reverse transcriptase inhibitor (P < 0.001) compared with those receiving lopinavir/ritonavir alone.

Conclusions

These results confirmed the interaction between lopinavir and efavirenz, and also demonstrated a significant interaction between the former drug [lopinavir] and nevirapine, resulting in lower C(trough) of lopinavir.

The authors conclude, “The wide inter-patient variability in this interaction suggests that therapeutic drug monitoring may be useful in optimizing the dose of lopinavir.”

Department of Pharmacokinetics, AP-HM Timone, Marseille, France.

03/31/04

Reference
C Solas and others. Therapeutic drug monitoring of lopinavir/ritonavir given alone or with a non-nucleoside reverse transcriptase inhibitor. British Journal of Clinical Pharmacology 57(4): 436-440. April 2004.