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The identification of pharmacogenetic factors that increase the susceptibility to clozapine-induced agranulocytosis or granulocytopenia (CIAG) has received increasing interest. The SLCO1B3-SCLO1B7 variant (rs149104283) and single amino acid changes in human leukocyte antigen (HLA) HLA-DQB1 (126Q) and HLA-B (158T) were associated with an increased risk of CIAG. In this study, we evaluated the effectiveness and cost-effectiveness of adding the SLCO1B3- SCLO1B7 to HLA variants as a new pharmacogenomic (PGx) approach and explored the evolution of a cohort of schizophrenic patients taking long-term clozapine as a third-line antipsychotic medication. The decision model included probabilistic and deterministic sensitivity analyses to assess the expected costs and quality-adjusted life-years (QALYs). The current monitoring scheme was compared with the PGx-guided strategy, where all patients underwent preemptively a genetic test before taking clozapine, over 10 years. By adding the SLCO1B3-SCLO1B7 variant into HLA variants, CIAG sensitivity increased from 36.0% to 43.0%, the specificity decreased from 89.0% to 86.9%, and the probability of cost-effectiveness improved from 74.1% to 87.8%. The incremental cost-effectiveness ratio was £16,215 per QALY and remained below the conventional decision threshold (£30,000 or US$50,000 per QALY). Therefore, the SLCO1B3-SCLO1B7 variant, as an additional risk allele to HLA variants, increases preemptive test sensitivity and improves the effectiveness and cost-effectiveness of PGx-guided clozapine administration. [ABSTRACT FROM AUTHOR]

Background: The pharmacokinetics of long-acting rilpivirine has mostly been studied in clinical trials, which do not fully address the uncertainties that arise in routine clinical situations., Aims and Methods: Our population analysis aims to establish percentile curves for rilpivirine concentrations in people with HIV (PWH) followed-up in a routine clinical setting, while identifying patient-related factors that may influence rilpivirine exposure. A total of 238 PWH enrolled in our nationwide multicenter observational study contributed to 1038 concentrations (186 and 852 concentrations after oral and intramuscular injection, respectively)., Results: Rilpivirine pharmacokinetics were best described by a two-compartment model with an oral to intramuscular relative bioavailability factor. A simple zero-order absorption process was retained for oral administration while a parallel first-order absorption was used for intramuscular administration, with 27.6% of the dose released via a fast absorption pathway and the remaining fraction via a slow absorption pathway. Our model estimated that long-acting rilpivirine reaches steady-state after 2.5 years and has an elimination half-life of 18 weeks, consistent with published estimates. In females, a 45.6% reduction in the proportion of the dose absorbed via the rapid absorption pathway was observed. However, this resulted in no more than 15% difference in trough concentrations (C trough ) compared to males, which was not considered to be clinically relevant., Conclusion: Overall, our model-based simulations showed that only approximately 50% of long-acting rilpivirine C trough would be above the 50 ng/mL threshold associated with optimal therapeutic response, while approximately 85% of C trough would be above the first quartile of concentrations observed in Phase III trials (32 ng/mL)., Competing Interests: MC reports grants and payment for expert testimony from Gilead, MSD, and ViiV and support for attending meetings from Gilead, paid to his institution. DB reports honoraria for advisory boards, lectures, and travel grants from the companies Gilead, ViiV, and MSD. HG has received unrestricted research grants from Gilead Sciences and ViiV Healthcare; fees for data and safety monitoring board membership from Merck; consulting/advisory board membership fees from Gilead Sciences, GSK, Johnson and Johnson, Janssen, Novartis, and ViiV Healthcare; and grants from the Yvonne Jacob Foundation, from the National Institutes of Health, and unrestricted research grants from Gilead Sciences. The institution of JD received grants from Gilead Sciences and ViiV. BS reports support for travel grants and advisory boards from Gilead Sciences and ViiV, paid to his institution. The institution of HF received educational grants from ViiV, MSD, AbbVie, Gilead, and Sandoz. MS reports advisory board payments to his institution by Gilead, MSD, ViiV, Moderna, and Pfizer. The institution of AR received grants from Gilead, support for attending meetings from Gilead and Pfizer, and advisory board fees from MSD and Moderna. CM has received speaker honoraria from ViiV, MSD, and Gilead. CD received travel grants for congress participation from Gilead. The institution of EB received grants from the Swiss National Science Foundation; grants from MSD; support for attending meetings from Gilead, MSD, ViiV, and Pfizer; and advisory board fees from Gilead, MSD, ViiV, Pfizer, Moderna, AstraZeneca, Abbvie, and Lilly. The institution of PS received honoraria for advisory board participation and support for attending meetings from ViiV and Gilead. None of those grants and supports was related to the submitted work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Thoueille, Saldanha, Schaller, Choong, Veuve, Munting, Cavassini, Braun, Günthard, Duran Ramirez, Surial, Furrer, Rauch, Ustero, Calmy, Stöckle, Di Benedetto, Bernasconi, Schmid, Marzolini, Girardin, Buclin, Decosterd and Guidi.)