Limited Sampling Strategies for the Estimation of Raltegravir Daily Exposure in HIV‐Infected Patients

Abstract

Stepwise multiple regression analyses were applied to 50 raltegravir pharmacokinetic profiles from 50 HIV patients with the goal to identify limited sampling strategies for the prediction of drug area under the time-concentration curve (AUC(0-12)). Raltegravir single sampling point-based equations failed to reliably predict daily drug exposure. Conversely, different algorithms based on few samples and associated with good correlation, acceptable bias, and imprecision with the measured raltegravir AUC(0-12) were identified. These models could used to predict raltegravir exposure for clinic or research purposes.

Is it time to revise antiretrovirals dosing? A pharmacokinetic viewpoint

“…It is more difficult to confirm this trend for novel drugs -namely darunavir, etravirine and maraviroc -simply because no clinical evidence is available to date correlating their plasma concentrations with toxicity. raltegravir exposure [23]. As confirmed by this and our previous findings, trough concentrations of raltegravir were associated with a very wide interpatient variability [22].…”

Comparison of the In Vivo Pharmacokinetics and In Vitro Dissolution of Raltegravir in HIV Patients Receiving the Drug by Swallowing or by Chewing

“…Indeed, phase II/III trials have shown that RAL plasma concentrations and drug exposure were correlated with the efficacy outcome, whereas no relevant clinical associations were found with the RAL C trough (11,13,16). The latter finding was not unexpected, given the failure of the RAL C trough to reliably predict daily drug exposure, expressed as RAL AUC 0-12 (5). In the present study, we have shown that patients taking RAL by swallowing whole tablets experienced a wide distribution in the main drug pharmacokinetic parameters.…”

“…For most antiretrovirals, TDM is usually performed by assessing the single plasma trough concentration (C trough ). However, this approach is not feasible for RAL, which requires routine assessment of the predicted area under the concentration-time curve (AUC) (5). The assessment of RAL plasma concentrations was therefore carried out as routine TDM based on the collection of blood samples within the first 4 h after the morning RAL dose.…”

“…This has also been confirmed by the results of the QDMRK trial (7), showing that plasma RAL concentrations correlate significantly with the likelihood of virologic response in patients given the drug once daily. Despite the lack of establishment of a well-defined therapeutic range for RAL, these studies indicate that a correlation may exist between the individual RAL plasma concentrations and the clinical outcome for HIV-infected patients, suggesting potential relevance of therapeutic drug monitoring (TDM) in selected situations.Limited studies in healthy volunteers and in HIV-infected patients have shown that RAL pharmacokinetics is characterized by high interpatient variability (3,5,11,13). Recently, we have shown that the pharmacokinetics of RAL in HIV-infected subjects is also characterized by high intrapatient variability (4).…”

“…Limited studies in healthy volunteers and in HIV-infected patients have shown that RAL pharmacokinetics is characterized by high interpatient variability (3,5,11,13). Recently, we have shown that the pharmacokinetics of RAL in HIV-infected subjects is also characterized by high intrapatient variability (4).…”