Variability of Raltegravir Plasma Levels in the Clinical Setting

Abstract

Therapeutic drug monitoring of raltegravir C_trough levels was carried out in the setting of the Raltegravir Switch for Toxicity or Adverse events (RASTA) trial, a randomized pilot study exploring a 48-week safety and efficacy of treatment switch to raltegravir associated with tenofovir/emtricitabine or abacavir/lamivudine in patients with regimens with optimal virologic control. Blood sampling for measurement of raltegravir plasma levels was carried out at weeks 4, 12, 24, 36 and 48. Plasma samples were analysed by a recently developed and validated UPLC-MS method. A total of 164 samples from 39 patients were assayed. Analysis for intra- and inter-subject variability was restricted to those patients with 4 or more determinations, including 30 patients and 142 determinations. The intra- and inter-subject variability measures were 85.9 and 124.6%, respectively, with an intra-/inter-subject variability ratio of 69%. We also analysed data from a subset of patients with well-documented adherence to protocol, defined as protocol compliant population, including 21 patients and 93 determinations. In this subpopulation, we estimated intra- and inter-subject variability of 79.87% and 110%, respectively, with an intra-/inter-subject variability ratio of 72.6%. This study confirms the notion that raltegravir is a highly variable drug according to the European Medicines Agency criteria. While this condition does not favour the adoption of therapeutic drug monitoring in the clinical practice, the latter is deemed useful in patients with drug plasma concentrations below or near the threshold level of efficacy (since intracellular raltegravir levels might be as low as 5% of the corresponding plasma levels), or to identify drug-drug interactions of potential clinical relevance.

Pharmacokinetic Drug–drug Interaction Study between Raltegravir and Citalopram

“…The difference in C max and AUC 0-12 h of raltegravir in the presence or absence of citalopram is more likely due to the high variability in raltegravir pharmacokinetics instead of an effect caused by citalopram. The extensive intra-and interindividual variability in the pharmacokinetics of raltegravir seen in our study is described by others also and consistent with the known pharmacokinetic profile of raltegravir [39][40][41]. A major contributor to the variability in raltegravir pharmacokinetics is pH dependent absorption and dissolution of raltegravir in the gastrointestinal tract [42].…”

Effect of ageing on antiretroviral drug pharmacokinetics using clinical data combined with modelling and simulation

“…Raltegravir was the only studied antiretroviral drugs for which data obtained from PLWH in our clinical study were mostly underpredicted by the model in contrast to published studies. This could possibly be explained by the known large variability of raltegravir plasma concentrations observed in clinical practice 34 . However, in the case of large variability, the model should over‐ and underpredict raltegravir plasma concentrations.…”

Impact of UGT1A1 polymorphisms on Raltegravir and its glucuronide plasma concentrations in a cohort of HIV-1 infected patients

“…In conclusion, most of the previous studies failed to demonstrate a correlation between RAL plasma exposure and UGT1A1*28 polymorphism. RAL is well known to have erratic pharmacokinetic profile with high intra- and inter- individual variability and coefficients of variations (CV) of 122–245% and 110–212% when considering the plasma concentrations within the same individual or between individuals, respectively 23 , 24 . This high degree of variability observed in the PK behavior of RAL combined with the small sample size of the above-mentioned cohorts 16 – 18 has a potential negative impact on the statistical power and might explain why the UGT1A1*28 allele is not always significantly associated with variations of RAL plasma exposure by hiding the true pharmacogenomic effect of this variant.…”