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

Abstract

The pharmacokinetics of raltegravir (RAL) in HIV patients is characterized by high interpatient/intrapatient variability. We investigated the potential contribution of the drug pharmaceutical formulation to RAL pharmacokinetics. We first compared in vivo the pharmacokinetics of RAL for 67 patients to whom the drug was administered by swallowing the intact tablet with those obtained from 13 HIV-infected patients who chewed the RAL tablet due to swallowing difficulties. Subsequently, we evaluated in vitro the dissolution of RAL tablets under different conditions. In the in vivo study, we found that patients given RAL by chewing the tablets presented pharmacokinetic profiles characterized by significantly higher RAL absorption than did patients receiving the drug by swallowing. The in vitro studies showed that when the whole tablets were exposed to an acidic medium, the release of RAL was very low, whereas when the tablets were crushed, the profiles presented significantly higher concentrations of RAL. Crushed tablets tested in water or in a pH 6.8 buffer exhibited prompt and complete dissolution of RAL. HIV-infected patients receiving RAL by chewing the tablet showed higher drug absorption and reduced pharmacokinetic variability compared with patients swallowing the intact tablet. This is related to problems in tablet disintegration and to erratic drug absorption. The amelioration of the RAL pharmaceutical formulation could improve drug pharmacokinetics. R altegravir (RAL) is the first approved integrase inhibitor targeting the strand transfer step of HIV integration (14). Studies in HIV treatment-experienced as well as in naive patients have shown that RAL-containing regimens have potent antiretroviral activity (2). Moreover, the favorable side effect profile in comparison to all other antiretrovirals, as well as the minimal impact on lipid homeostasis, has made RAL a strong option for the treatment of an array of HIV-infected patients (2). Unexpected negative results from recent clinical trials in which RAL-based arms were associated with higher than expected virologic failure rates compared with protease inhibitor-based therapies, however, have raised some concerns about the clinical efficacy of RAL (7,12,15).A clear relationship between clinical efficacy and RAL plasma concentrations has not been identified yet, and the pharmacokinetics of the drug appears to have less influence on treatment outcome than other covariates (e.g., baseline HIV RNA and use of other active agents in optimized background therapy) (2). Nevertheless, this concept has been challenged by recent findings. Indeed, a prospective study involving 106 HIV-infected patients experiencing treatment failure under RAL-containing regimens has shown that plasma RAL exposure significantly influences the drug antiviral activity and the eventual selection of resistance mutations (11). 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 respon...

Mucosal tissue pharmacokinetics of the integrase inhibitor raltegravir in a humanized mouse model: Implications for HIV pre-exposure prophylaxis

“…The plasma T max of 2h observed in hu-mice was comparable to that seen in human studies (36–40). Variability in plasma drug concentrations as seen in human studies was also observed in hu-mice with CV% of 84% at 8h and 150% at 24h and 48h (Supplementary Table 1) (36,37,40–44). This is not likely due to the levels of human cell reconstitutions in hu-mice since mice with similar human cell levels were used.…”

Single‐ and Multiple‐Dose Pharmacokinetics of Once‐Daily Formulations of Raltegravir

“…It has been previously reported that the 400-mg tablet dissolution is relatively slow; the authors speculated that because of the pH-dependent solubility, disintegration of the tablet may not readily take place in the stomach, whereas dissolution slowly starts in the more favorable intestinal pH environment. 22 In the same study the authors reported somewhat higher bioavailability (ß25%, somewhat more pronounced effect on C max ) from crushed tablets compared with intact tablets. Given the increase in bioavailability of the 600-mg tablets in the current study, it is reasonable to also suggest faster disintegration and subsequently dissolution in vivo for the new formulation, consistent with the formulation design.…”

Pharmacokinetic and pharmacodynamic evaluation of raltegravir and experience from clinical trials in HIV-positive patients

“…A in vitro--in vivo extrapolation model was developed and it predicted raltegravir pharmacokinetics in virtual individuals: different gastrointestinal pH profiles and transit times correlated with absorption rates [9]. Chewing the film-coated tablets (both once and twice daily) has been associated with higher drug absorption and reduced pharmacokinetic variability compared with swallowing the intact tablet; this has been advocated as a way of overcoming the rifampicin interaction, although conflicting results recently emerged [10][11][12].…”