Are lopinavir and efavirenz serum concentrations in HIV-infected children in the therapeutic range in clinical practice?

BACKGROUND: In antiretroviral treatment the role of therapeutic drug monitoring via measurement of serum levels remains unclear, especially in children. AIM: To quantify exposure to LPV and EFV in children receiving therapy in a routine clinical setting in order to identify risk factors associated with inadequate drug exposure. METHOD: A prospective study was conducted in a routine clinical setting in Tygerberg Children's Hospital, South Africa. A total of 53 random serum levels were analyzed. Serum concentrations were determined by an established high-performance liquid chromatography method. RESULTS: Of 53 HIV-infected children treated with lopinavir (n = 29, median age 1·83 y) or efavirenz (n = 24, median age 9·3 years), 12 showed serum levels outside the therapeutic range (efavirenz) or below Cmin (lopinavir). Low bodyweight, rifampicin co-treatment, and significant comorbidity were potential risk factors for inadequate drug exposure. CONCLUSION: These findings, together with previous studies, indicate that therapeutic drug monitoring can improve the management of antiretroviral therapy in children at risk.

The role of therapeutic drug monitoring in the management of patients with human immunodeficiency virus infection.

Therapeutic drug monitoring (TDM) is a well-established method to optimize dosing regimens in individual patients for drugs that are characterized by a narrow therapeutic range and large interindividual pharmacokinetic variability. For some antiretroviral drugs, mainly nonnucleoside reverse transcriptase inhibitors and protease inhibitors, TDM has been proposed as a means to improve the response in human immunodeficiency virus-infected patients. In contrast, nucleoside reverse transcriptase inhibitors do not show a predictable plasma concentration-response (toxicity, efficacy) relationship, and intracellular analyses are expensive. Therefore, TDM is generally not recommended for this class of drugs. TDM has been successfully applied in the clinical practice for certain antiretroviral drugs, but there are ongoing research efforts on the use and refinement of TDM for human immunodeficiency virus treatment, and convincing data from randomized trials are still needed. The best pharmacokinetic measures of drug exposure such as trough and peak concentrations or concentration ratios have not been unambiguously established.

Permeation of four oral drugs through human intestinal mucosa.

The pharmaceutical industry is in need of rapid and accurate methods to screen new drug leads for intestinal permeability potential in the early stages of drug discovery. Excised human jejunal mucosa was used to investigate the permeability of the small intestine to four oral drugs, using a flow-through diffusion system. The four drugs were selected as representative model compounds of drug classes 1 and 3 according to the biopharmaceutics classification system (BCS). The drugs selected were zidovudine, propranolol HCl, didanosine, and enalapril maleate. Permeability values from our in vitro diffusion model were compared with the BCS permeability classification and in vivo and in vitro gastrointestinal drug permeability. The flux rates of the four drugs were influenced by the length of the experiment. Both class 1 drugs showed a significantly higher mean flux rate between 2 and 6 h across the jejunal mucosa compared to the class 3 drugs. The results are therefore in line with the drugs' BCS classification. The results of this study show that the permeability values of jejunal mucosa obtained with the flow-through diffusion system are good predictors of the selected BCS class 1 and 3 drugs' permeation, and it concurred with other in vitro and in vivo studies.