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Aims: The pharmacokinetics of doravirine has been studied in clinical trials but not in real‐world settings. Our study aims to characterize and identify factors influencing doravirine (a CYP3A4 substrate) pharmacokinetics in real‐world people with HIV (PWH). Methods: A total of 174 doravirine concentrations measured in 146 PWH followed up in the therapeutic drug monitoring (TDM) program at the University Hospital of Lausanne (Switzerland) between 2019 and 2023 were included in the analysis. Demographic data, clinical information and comedications were recorded during the routine SHCS visits (every 3–6 months). Population pharmacokinetic analysis and Monte Carlo simulations to investigate the clinical significance of the covariates retained in the final model were performed using NONMEM. Results: A one‐compartment model with first‐order absorption and linear elimination best described doravirine pharmacokinetics. Potent CYP3A4 inhibitors and, to a lesser extent age, were the only tested covariates to significantly impact doravirine clearance (CL). Potent CYP3A4 inhibitors reduced CL by 50%, and a 30% decrease in CL was observed in an 80‐year‐old compared with a 55‐year‐old PWH. The effect of potent CYP3A4 inhibitors was prominent, explaining 59% of between‐subject variability in CL. Model‐based simulations predicted 2.8‐fold and 1.6‐fold increases in median steady‐state trough and maximum doravirine concentrations, respectively, when a potent CYP3A4 inhibitor was co‐administered. Conclusions: Our findings show that potent CYP3A4 inhibitors and age influence doravirine pharmacokinetics. However, given the good tolerability of doravirine, dosing adjustment of doravirine is probably not mandatory in those situations. TDM remains useful essentially in specific clinical situations, such as hepatic impairment, suspected nonadherence or pregnancy. [ABSTRACT FROM AUTHOR]

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: Model-informed precision dosing (MIPD) combines population pharmacokinetic knowledge with therapeutic drug monitoring (TDM) to optimize dosage adjustment. It could improve target concentration attainment over empirical TDM, still widely practised for broad-spectrum antibiotics., Objectives: To evaluate the respective performance of TDM and MIPD in achieving target piperacillin exposure., Methods: Measurements from 80 courses of intermittent piperacillin infusions, each with two TDM samples, were retrospectively submitted to our MIPD software TUCUXI. We considered six dosage adjustment strategies: identical dosage for all (4000 mg q8h), actual initial dosage (chart-based), actual empirical adjustment following first TDM, a priori MIPD-based dosage, a posteriori MIPD-based adjustment after first TDM and MIPD including both TDM measurements. Dosing strategies were compared regarding daily dosage, trough levels distribution and PTA (with target trough 8-32 mg/L)., Results: Median trough concentration fell within 8-32 mg/L for all strategies except a priori MIPD-based dosage (42 mg/L). Distributions of trough concentrations predicted with the six dosage adjustment strategies showed significant differences, with both a posteriori MIPD-based strategies best reducing their standard deviation (P < 0.001). PTA of 32%, 32%, 55%, 29%, 83% and 94% were estimated, respectively for the six strategies (P < 0.001). Poor performance of a priori MIPD-based dosage did not hinder a posteriori MIPD-based strategies from significantly improving target attainment., Conclusions: Whilst empirical TDM improves exposure standardization and target attainment compared with no TDM, MIPD can still bring further improvement. Prospective trials remain warranted to confirm MIPD benefits not only on target attainment but also on clinical endpoints., (© The Author(s) 2025. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.)

The 2023-2024 updates on teratovigilance, with a focus on antiseizure medications, highlight several key points. American medical societies have revised their recommendations: maintaining effective seizure control is essential for both maternal and fetal health; lamotrigine, levetiracetam, and oxcarbazepine are preferred first-line treatments, whereas valproic acid and topiramate should be avoided if possible. In March 2024, an update on topiramate indicated an increased risk of neurodevelopmental disorders with prenatal exposure. For autism spectrum disorders specifically, a recent study did not find evidence linking topiramate to autism spectrum disorder. Lastly, a potential risk of neurodevelopmental disorders in children with fathers who used valproic acid has been suggested, but remains unconfirmed., Competing Interests: le Dr Jan Novy a participé à des Advisory Boards pour Angelini Pharma, Jazz Pharma et UCB Pharma. Les autres auteurs n’ont déclaré aucun conflit d’intérêts en relation avec cet article.

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.)

Background: The heterogeneous clinical presentation of graft microvascular inflammation poses a major challenge to successful kidney transplantation. The effect of microvascular inflammation on allograft outcomes is unclear., Methods: We conducted a cohort study that included kidney-transplant recipients from more than 30 transplantation centers in Europe and North America who had undergone allograft biopsy between 2004 and 2023. We integrated clinical and pathological data to classify biopsy specimens according to the 2022 Banff Classification of Renal Allograft Pathology, which includes two new diagnostic categories: probable antibody-mediated rejection and microvascular inflammation without evidence of an antibody-mediated response. We then assessed the association between the newly recognized microvascular inflammation phenotypes and allograft survival and disease progression., Results: A total of 16,293 kidney-transplant biopsy specimens from 6798 patients were assessed. We identified the newly recognized microvascular inflammation phenotypes in 788 specimens, of which 641 were previously categorized as specimens with no evidence of rejection. As compared with patients without rejection, the hazard ratio for graft loss was 2.1 (95% confidence interval [CI], 1.5 to 3.1) among patients with microvascular inflammation without evidence of an antibody-mediated response and 2.7 (95% CI, 2.2 to 3.3) among patients with antibody-mediated rejection. Patients with a diagnosis of probable antibody-mediated rejection had a higher risk of graft failure beyond year 5 after biopsy than those without rejection (hazard ratio, 1.7; 95% CI, 0.8 to 3.5). Patients with a diagnosis of either newly recognized microvascular inflammation phenotype had a higher risk of progression of transplant glomerulopathy during follow-up than patients without microvascular inflammation., Conclusions: Microvascular inflammation in kidney allografts includes distinct phenotypes, with various disease progression and allograft outcomes. Our findings support the clinical use of additional rejection phenotypes to standardize diagnostics for kidney allografts. (Funded by OrganX. ClinicalTrials.gov number, NCT06496269.)., (Copyright © 2024 Massachusetts Medical Society.)

Long-acting cabotegravir has been studied mainly in the stringent framework of clinical trials, which does not necessarily reflect the situation of people with HIV (PWH) in routine clinical settings. The present population pharmacokinetic analysis aims to build real-world reference percentile curves of cabotegravir concentrations, accounting for patient-related factors that may affect cabotegravir exposure. The second objective is to simulate whether dosing interval adjustments of cabotegravir could be considered in specific subpopulations. Overall, 238 PWH contributed to 1,038 cabotegravir levels (186 during the initial oral administration phase and 852 after intramuscular injection). Cabotegravir pharmacokinetics was best described using a one-compartment model with distinct first order-absorption for oral and intramuscular administrations, and identical volume and clearance. Our model showed almost 40% faster absorption and 30% higher clearance than previously reported, resulting in a time to steady-state of 8 months and an elimination half-life of 4.6 weeks for long-acting cabotegravir. Sex and body mass index significantly influenced absorption, and bodyweight affected clearance. Model-based simulations showed that cabotegravir trough concentrations in females were 25% lower 4 weeks after the intramuscular loading dose, but 42% higher during the late maintenance phase. Finally, simulations indicated that in females, despite significantly higher cabotegravir concentrations, longer intervals between injections may not consistently ensure levels above the 4-fold protein-adjusted 90% inhibitory target concentration., (© 2024 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

The list of drugs whose abrupt discontinuation is likely to induce withdrawal symptoms or a rebound in the pathology being treated is not limited to psychotropic drugs. It includes a number of somatic drugs (e.g. proton pump inhibitors, opioids, triptans, fingolimod, corticosteroids, antiepileptics, nootropics, antiparkinsonians, denosumab, beta-blockers, laxatives, nasal vasoconstrictors, etc.). This type of unintended effect, often underestimated, generally results from a drug-induced homeostatic imbalance that persists after the drug has been discontinued. Taking this risk into account right from the initial prescription should make it possible to prevent such complications, by encouraging intermittent use of the drug, or by applying a very gradual reduction in dosage when a regular treatment is stopped., Competing Interests: Les auteurs n’ont déclaré aucun conflit d’intérêts en relation avec cet article.

Aims: The aim of this study was to assess the cost-effectiveness of eight common diagnostic work-up strategies for coronary heart disease (CHD) in patients with stable angina symptoms in Switzerland., Methods and Results: A decision analytical model was used to perform a cost-effectiveness comparison of eight common multitest strategies to diagnose CHD using combinations of four diagnostic techniques: exercise treadmill test (ETT), single-photon emission computed tomography (SPECT), cardiac magnetic resonance imaging (CMR), and coronary angiography (CA). We used a Markov state transition model to extrapolate the results over a life-time horizon, from a third-party payer perspective. We used a CHD prevalence rate of 39% in patients and a base-case scenario with 60-year-old male patients with intermediate symptom severity Canadian Cardiovascular Society grading of angina pectoris 2 and at least one cardiovascular (CV) risk factor but without a history of myocardial infarction and without need for revascularization. Among the eight work-up strategies, one strategy was dominant, i.e. least costly and most effective: ETT followed by CMR if the ETT result was inconclusive and then CA if the CMR result was positive or inconclusive. The CMR features a favourable balance between false-negative diagnoses, associated with an elevated risk of CV events, and false-positive diagnoses, leading to unnecessary CA and related mortality. Key parameters guiding the diagnostic strategy are the prevalence of CHD in patients with angina symptoms and the diagnostic costs of CA and CMR., Conclusion: Cardiac magnetic resonance imaging appears to be a cost-effective work-up strategy compared with other regimens using SPECT or direct CA. Cardiac magnetic resonance imaging should be more widely recommended as a diagnostic procedure for patients with suspected angina symptoms.