Population Pharmacokinetics of Cabotegravir Following Oral Administration and Long-Acting Intramuscular Injection in Real-World People with HIV.

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.

Guidance for the Interpretation of Long-Acting Cabotegravir and Rilpivirine Concentrations Based on Real-World Therapeutic Drug Monitoring Data and Documented Failures.

The interpretation of long-acting cabotegravir and rilpivirine concentrations is complicated by the lack of consensus on the threshold to consider. Building on real-world therapeutic drug monitoring data and documented virologic failures, this article provides a reappraisal of the existing thresholds and guidance for the interpretation of cabotegravir and rilpivirine concentrations.

Real-world trough concentrations and effectiveness of long-acting cabotegravir and rilpivirine: a multicenter prospective observational study in Switzerland.

Background: The efficacy and tolerability of long-acting cabotegravir and rilpivirine were demonstrated in Phase III trials. However, low concentrations combined with other risk factors have been associated with an increased risk of virologic failure. This study aims to verify whether drug concentrations measured in a real-world setting are consistent with those previously reported. Methods: SHCS-879 is a nationwide observational study within the Swiss HIV Cohort Study for the monitoring of people with HIV (PWH) on long-acting cabotegravir plus rilpivirine. Samples were collected from March 2022 to March 2023. Findings: Overall, 725 samples were obtained from 186 PWH. Our data show a large inter-individual variability in cabotegravir and rilpivirine concentrations, with some individuals exhibiting repeatedly low concentrations. Rilpivirine trough concentrations were consistent with those from Phase III trials, while cabotegravir concentrations were lower. The first concentrations quartile was only slightly above the target of 664 ng/mL. Exploratory statistical analyses found 35% (p < 0·01) lower cabotegravir trough in males compared to females. Overall, 172 PWH (92%) remained suppressed and three experienced virologic failures (1·6%), of those, two had sub-optimal drug exposure. No association was found between low trough levels and detectable viral load. Interpretation: Real-world cabotegravir concentrations are substantially lower than previously reported. However, these concentrations appear sufficient to ensure sustained virological suppression in almost every PWH. These reassuring data challenge the rather conservative thresholds adopted to date, which may raise unnecessary concerns. Yet, our study reveals that some PWH have repeatedly very low drug levels, for reasons that remain to be elucidated. Funding: This work was funded by the Swiss National Science Foundation, grant number N◦ 324730_192449. This study received no support from pharmaceutical industries. This study was performed within the framework of the Swiss HIV Cohort Study, supported by the Swiss National Science Foundation (grant #201369), by SHCS project #879, and by the SHCS research foundation. The SHCS data were gathered by the Five Swiss University Hospitals, two Cantonal Hospitals, 15 affiliated hospitals and 36 private physicians (listed in http://www.shcs.ch/180-health-care-providers).

Population pharmacokinetic analysis of doravirine in real-world people with HIV.

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.

A Single-Run HPLC-MS Multiplex Assay for Therapeutic Drug Monitoring of Relevant First- and Second-Line Antibiotics in the Treatment of Drug-Resistant Tuberculosis.

The treatment of drug-resistant Mycobacterium tuberculosis relies on complex antibiotic therapy. Inadequate antibiotic exposure can lead to treatment failure, acquired drug resistance, and an increased risk of adverse events. Therapeutic drug monitoring (TDM) can be used to optimize the antibiotic exposure. Therefore, we aimed to develop a single-run multiplex assay using high-performance liquid chromatography-mass spectrometry (HPLC-MS) for TDM of patients with multidrug-resistant, pre-extensively drug-resistant and extensively drug-resistant tuberculosis. A target profile for sufficient performance, based on the intended clinical application, was established and the assay was developed accordingly. Antibiotics were analyzed on a zwitterionic hydrophilic interaction liquid chromatography column and a triple quadrupole mass spectrometer using stable isotope-labeled internal standards. The assay was sufficiently sensitive to monitor drug concentrations over five half-lives for rifampicin, rifabutin, levofloxacin, moxifloxacin, bedaquiline, linezolid, clofazimine, terizidone/cycloserine, ethambutol, delamanid, pyrazinamide, meropenem, prothionamide, and para-amino salicylic acid (PAS). Accuracy and precision were sufficient to support clinical decision making (≤±15% in clinical samples and ±20-25% in spiked samples, with 80% of future measured concentrations predicted to fall within ±40% of nominal concentrations). The method was applied in the TDM of two patients with complex drug-resistant tuberculosis. All relevant antibiotics from their regimens could be quantified and high-dose therapy was initiated, followed by microbiological conversion. In conclusion, we developed a multiplex assay that enables TDM of the relevant first- and second-line anti-tuberculosis medicines in a single run and was able to show its applicability in TDM of two drug-resistant tuberculosis patients.

Development and validation of a multiplex HPLC-MS/MS assay for the monitoring of JAK inhibitors in patient plasma.

Janus kinase inhibitors (JAKi) are oral small molecules used in the treatment of a broad spectrum of autoimmune and myeloproliferative diseases. JAKi exhibit significant intra- and inter-individual pharmacokinetic variabilities, due to fluctuations in compliance with oral treatments and their metabolism essentially driven by cytochrome P450 enzymes. Intrinsically, JAKi have dose-response relationship and narrow therapeutic index: therapeutic drug monitoring (TDM) is expected to optimize and adapt their dosage regimen in order to resolve problems of efficacy and tolerance linked to dose and safety. A sensitive analytical method using multiplex high-performance liquid-chromatography coupled to tandem mass spectrometry (HPLC-MS/MS) was developed and validated for the simultaneous quantification in plasma of the 6 major currently used JAKi, namely abrocitinib, baricitinib, fedratinib, ruxolitinib, tofacitinib, and upadacitinib. Plasma samples are subjected to protein precipitation with MeOH, using stable isotopically labelled internal standards. The separation of JAKi in supernatants diluted 1:1 with ultrapure H2O was performed using a C18 column Xselect HSS T3 2.5 µm, 2.1x150 mm using a mobile phase composed of formic acid (FA) 0.2% and acetonitrile (+FA 0.1%) in gradient mode. The analytical run time for the multiplex assay was 7 min. JAKi drugs were monitored by electrospray ionization in the positive mode followed by triple-stage quadrupole MS/MS analysis. The method was validated according to SFSTP and ICH guidelines over the clinically relevant concentration ranges (0.5-200 ng/mL for abrocitinib, baricitinib and upadacitinib; 1-400 ng/mL for tofacitinib; 0.5-400 ng/mL for ruxolitinib, and 10-800 ng/mL for fedratinib). This multiplex HPLC-MS/MS assay achieved good performances in term of trueness (91.1-113.5%), repeatability (3.0-9.9%), and intermediate precision (4.5-11.3%). We developed and validated a highly sensitive method for the multiplex quantification of the JAKi abrocitinib, baricitinib, fedratinib, ruxolitinib, tofacitinib, and upadacitinib in human plasma. The method will be applied for prospective clinical pharmacokinetic studies to determine whether TDM programs for JAKi based on residual drug concentrations can be recommended using disease-specific therapeutic ranges.

Population pharmacokinetic analysis of lopinavir in HIV negative individuals exposed to SARS-CoV-2: a COPEP (COronavirus Post-Exposure Prophylaxis) sub-study.

BACKGROUND: Lopinavir/ritonavir (LPV/r) is a drug traditionally used for the treatment of HIV that has been repurposed as a potential post-exposure prophylaxis agent against COVID-19 in the COronavirus Post-Exposure Prophylaxis (COPEP) study. The present analysis aims to evaluate LPV levels in individuals exposed to SARS-CoV-2 versus people living with HIV (PLWH) by developing a population pharmacokinetic (popPK) model, while characterizing external and patient-related factors that might affect LPV exposure along with dose-response association. METHODS: We built a popPK model on 105 LPV concentrations measured in 105 HIV-negative COPEP individuals exposed to SARS-CoV-2, complemented with 170 LPV concentrations from 119 PLWH followed in our routine therapeutic drug-monitoring programme. Published LPV popPK models developed in PLWH and in COVID-19 patients were retrieved and validated in our study population by mean prediction error (MPE) and root mean square error (RMSE). The association between LPV model-predicted residual concentrations (Cmin) and the appearance of the COVID-19 infection in the COPEP participants was investigated. RESULTS: A one-compartment model with linear absorption and elimination best described LPV concentrations in both our analysis and in the majority of the identified studies. Globally, similar PK parameters were found in all PK models, and provided close MPEs (from -19.4% to 8.0%, with a RMSE of 3.4% to 49.5%). No statistically significant association between Cmin and the occurrence of a COVID-19 infection could be detected. CONCLUSION: Our analysis indicated that LPV circulating concentrations were similar between COPEP participants and PLWH, and that published popPK models described our data in a comparable way.

Population pharmacokinetic modelling to characterize the effect of chronic kidney disease on tenofovir exposure after tenofovir alafenamide administration.

BACKGROUND: Tenofovir alafenamide is gradually replacing tenofovir disoproxil fumarate, both prodrugs of tenofovir, in HIV prevention and treatment. There is thus an interest in describing tenofovir pharmacokinetics (PK) and its variability in people living with HIV (PLWH) under tenofovir alafenamide in a real-life setting. OBJECTIVES: To characterize the usual range of tenofovir exposure in PLWH receiving tenofovir alafenamide, while assessing the impact of chronic kidney disease (CKD). METHODS: We conducted a population PK analysis (NONMEM®) on 877 tenofovir and 100 tenofovir alafenamide concentrations measured in 569 PLWH. Model-based simulations allowed prediction of tenofovir trough concentrations (Cmin) in patients having various levels of renal function. RESULTS: Tenofovir PK was best described using a one-compartment model with linear absorption and elimination. Creatinine clearance (CLCR, estimated according to Cockcroft and Gault), age, ethnicity and potent P-glycoprotein inhibitors were statistically significantly associated with tenofovir clearance. However, only CLCR appeared clinically relevant. Model-based simulations revealed 294% and 515% increases of median tenofovir Cmin in patients with CLCR of 15-29 mL/min (CKD stage 3), and less than 15 mL/min (stage 4), respectively, compared with normal renal function (CLCR = 90-149 mL/min). Conversely, patients with augmented renal function (CLCR > 149 mL/min) had a 36% decrease of median tenofovir Cmin. CONCLUSIONS: Kidney function markedly affects circulating tenofovir exposure after tenofovir alafenamide administration in PLWH. However, considering its rapid uptake into target cells, we suggest only a cautious increase of tenofovir alafenamide dosage intervals to 2 or 3 days only in case of moderate or severe CKD, respectively.

Precision Oncology by Point-of-Care Therapeutic Drug Monitoring and Dosage Adjustment of Conventional Cytotoxic Chemotherapies: A Perspective.

Therapeutic drug monitoring (TDM) of conventional cytotoxic chemotherapies is strongly supported yet poorly implemented in daily practice in hospitals. Analytical methods for the quantification of cytotoxic drugs are instead widely presented in the scientific literature, while the use of these therapeutics is expected to keep going for longer. There are two main issues hindering the implementation of TDM: turnaround time, which is incompatible with the dosage profiles of these drugs, and exposure surrogate marker, namely total area under the curve (AUC). Therefore, this perspective article aims to define the adjustment needed from current to efficient TDM practice for cytotoxics, namely point-of-care (POC) TDM. For real-time dose adjustment, which is required for chemotherapies, such POC TDM is only achievable with analytical methods that match the sensitivity and selectivity of current methods, such as chromatography, as well as model-informed precision dosing platforms to assist the oncologist with dose fine-tuning based on quantification results and targeted intervals.

Anticancer Activities of Novel Nicotinamide Phosphoribosyltransferase Inhibitors in Hematological Malignancies.

Targeting cancer cells that are highly dependent on the nicotinamide adenine dinucleotide (NAD+) metabolite is a promising therapeutic strategy. Nicotinamide phosphoribosyltransferase (NAMPT) is the rate-limiting enzyme catalyzing NAD+ production. Despite the high efficacy of several developed NAMPT inhibitors (i.e., FK866 (APO866)) in preclinical studies, their clinical activity was proven to be limited. Here, we report the synthesis of new NAMPT Inhibitors, JJ08, FEI191 and FEI199, which exhibit a broad anticancer activity in vitro. Results show that these compounds are potent NAMPT inhibitors that deplete NAD+ and NADP(H) after 24 h of drug treatment, followed by an increase in reactive oxygen species (ROS) accumulation. The latter event leads to ATP loss and mitochondrial depolarization with induction of apoptosis and necrosis. Supplementation with exogenous NAD+ precursors or catalase (ROS scavenger) abrogates the cell death induced by the new compounds. Finally, in vivo administration of the new NAMPT inhibitors in a mouse xenograft model of human Burkitt lymphoma delays tumor growth and significantly prolongs mouse survival. The most promising results are collected with JJ08, which completely eradicates tumor growth. Collectively, our findings demonstrate the efficient anticancer activity of the new NAMPT inhibitor JJ08 and highlight a strong interest for further evaluation of this compound in hematological malignancies.

Development and validation of a liquid chromatography coupled to tandem mass spectrometry method for the monitoring of temsavir plasma concentrations in people living with HIV.

A majority of people living with HIV (PLWH) now have access to HIV treatment with high antiviral potency and favorable tolerability profile. However, in some treatment experienced PLWH viral strains resistant to major current classes of antiretrovirals have emerged, usually due to periods with continued virus replication in the presence of failing drug regimens and thus selection pressure. In such context, new treatment options are therefore needed. Fostemsavir (RUKOBIA®) is the prodrug of temsavir, a first-in-class oral attachment inhibitor approved for the treatment of heavily treatment-experienced adults with multidrug-resistant HIV-1 infection. In this case RUKOBIA® is part of a complex regimen of antiretroviral drugs, often in addition to other drugs for chronic co-morbidities (e.g., heart disease, diabetes mellitus, hepatic and renal impairment, etc). In such a multi-drug regimen context, therapeutic drug monitoring (TDM) of temsavir can be necessary to exclude or adjust for relevant drug-drug interactions. A highly selective assay by liquid chromatography method coupled to tandem mass spectrometry (LC-MS/MS) was therefore developed for the quantification of temsavir in human plasma. A convenient sample preparation using protein precipitation with acetonitrile followed by supernatant dilution was carried out. Temsavir and fostemsavir were separated in less than 2 min using a multi-step UPLC gradient, thus ensuring adequate quantification of temsavir. The assay for the quantification of temsavir was extensively validated over the large range of clinically relevant concentrations from 1 to 10,000 ng/mL, in accordance with international bioanalytical method guidelines. The method achieves excellent performance in terms of trueness (99.7 - 105.3%), repeatability and intermediate precision (both from 1.6% to 5.8%). This LC-MS/MS method is now part of the routine analyses of the Laboratory of the Service of Clinical Pharmacology of Lausanne (CHUV), Switzerland, as an integrated part of our general TDM Service for antiretrovirals.

Treatment-emergent adverse events and antiseizure medication actual drug load.

OBJECTIVE: The correlation between treatment-emergent adverse events (TEAE) and antiseizure medication (ASM) drug load is a controversial topic. Previous studies used daily defined dosage (DDD) to measure drug load. We aim to assess if ASM adjusted to body weight and plasma levels were associated with TEAE. METHODS: We analyzed clinical visits of a trial on therapeutic drug monitoring in outpatients with epilepsy. TEAE, treatment, and its changes, as well as ASM plasma levels, were recorded at each visit. Each medication level was stratified according to its position in relation to its proposed reference range (below, in the lower half, upper half, or above). RESULTS: We analyzed 424 visits (151 participants). Treatment-emergent adverse events were reported in 84 (20%) visits. There was no significant difference when comparing visits with TEAE with those without TEAE in terms of ASM drug load (calculated with DDD), corrected for body weight, their changes since the last visit, as well as summed plasma levels compared to reference ranges. SIGNIFICANCE: Actual drug load seems not to represent a major determinant of TEAE recorded during routine visits, even when accounting thoroughly for the patient's exposure to the treatment. The use of structured questionnaires and neuropsychometric tests may assess more accurately the potential consequences of drug loads.

Real-Life Therapeutic Concentration Monitoring of Long-Acting Cabotegravir and Rilpivirine: Preliminary Results of an Ongoing Prospective Observational Study in Switzerland.

SHCS#879 is an ongoing Switzerland-wide multicenter observational study conducted within the Swiss HIV Cohort Study (SHCS) for the prospective follow-up of people living with HIV (PLWH) receiving long-acting injectable cabotegravir-rilpivirine (LAI-CAB/RPV). All adults under LAI-CAB/RPV and part of SHCS are enrolled in the project. The study addresses an integrated strategy of treatment monitoring outside the stringent frame of controlled clinical trials, based on relevant patient characteristics, clinical factors, potential drug-drug interactions, and measurement of circulating blood concentrations. So far, 91 blood samples from 46 PLWH have been collected. Most individuals are less than 50 years old, with relatively few comorbidities and comedications. The observed concentrations are globally in accordance with the available values reported in the randomized clinical trials. Yet, low RPV concentrations not exceeding twice the reported protein-adjusted 90% inhibitory concentration have been observed. Data available at present confirm a considerable between-patient variability overall. Based on the growing amount of PK data accumulated during this ongoing study, population pharmacokinetic analysis will characterize individual concentration-time profiles of LAI-CAB/RPV along with their variability in a real-life setting and their association with treatment response and tolerability, thus bringing key data for therapeutic monitoring and precision dosage adjustment of this novel long-acting therapy.

Valproate in status epilepticus: Correlation between loading dose, serum levels, and clinical response.

BACKGROUND AND PURPOSE: Intravenous valproate (VPA) is an established treatment of status epilepticus (SE), but optimal loading dose was not fully assessed. We aimed at analyzing the correlation between VPA loading dose and subsequent plasma levels with clinical response in SE. METHODS: This was a retrospective study in one referral center of all consecutive VPA-naïve SE episodes treated with VPA between January 2013 and June 2019, in which total VPA trough plasma levels after intravenous loading dose were available. Response to VPA, defined as last antiseizure medication introduced before SE resolution (without the need for additional treatment), was correlated with VPA loading dose and trough level. Correlations were adjusted for other SE characteristics. RESULTS: Among 128 SE episodes, 53 (41%) responded to VPA. Median VPA loading dose was 25.2 mg/kg (range, 7-58 mg/kg). Loading doses and total plasma levels were not associated with the probability of response or mortality. Correcting for other possible confounders (number of previously tried treatment, demographics, SE severity) did not alter these findings. Only 3.8% of SE episodes that responded to VPA received >30 mg/kg. CONCLUSIONS: A high loading dose (>30 mg/kg) is not associated with a greater response rate in patients with SE. Therefore, it seems to bring little benefit. If confirmed in further studies, a dosage of 25-30 mg/kg appears adequate in SE.

Long-acting antiretrovirals: a new era for the management and prevention of HIV infection.

The long-acting antiretroviral cabotegravir and rilpivirine combination has just received FDA, EMA and Health Canada approval. This novel drug delivery approach is about to revolutionize the therapy of people living with HIV, decreasing the 365 daily pill burden to only six intramuscular injections per year. In addition, islatravir, a first-in-class nucleoside reverse transcriptase translocation inhibitor, is intended to be formulated as an implant with a dosing interval of 1 year or more. At present, long-acting antiretroviral therapies (LA-ARTs) are given at fixed standard doses, irrespectively of the patient's weight and BMI, and without consideration for host genetic and non-genetic factors likely influencing their systemic disposition. Despite a few remaining challenges related to administration (e.g. pain, dedicated medical procedure), the development and implementation of LA-ARTs can overcome long-term adherence issues by improving patients' privacy and reducing social stigma associated with the daily oral intake of anti-HIV treatments. Yet, the current 'one-size-fits-all' approach does not account for the recognized significant inter-individual variability in LA-ART pharmacokinetics. Therapeutic drug monitoring (TDM), an important tool for precision medicine, may provide physicians with valuable information on actual drug exposure in patients, contributing to improve their management in real life. The present review aims to update the current state of knowledge on these novel promising LA-ARTs and discusses their implications, particularly from a clinical pharmacokinetics perspective, for the future management and prevention of HIV infection, issues of ongoing importance in the absence of curative treatment or an effective vaccine.

Therapeutic drug monitoring of newer generation antiseizure medications at the point of treatment failure.

PURPOSE: The benefit of therapeutic drug monitoring (TDM) of newer generation antiseizure medications (ASM) has been little studied. A recent randomized study suggested that TDM at each medical visit did not bring a significant benefit, but the study did not investigate TDM in cases of treatment failure. Accordingly, we realized a post hoc analysis of this trial. METHODS: We analyzed 282 TDMs in 136 patients. We compared TDM performed at visits after treatment failure versus without treatment failure, reporting the proportion of drug levels out of range and the prescriber's adherence to dosage recommendations according to measured drug levels. RESULTS: There was no statistical difference in terms of proportion of out of range plasma drug levels (47% vs 50%, p = 0.7) or adherence of prescribers to the clinical pharmacologists' dosage recommendations (21% vs 30%, p = 0.6) between visits after treatment failure and visits without treatment failure, respectively. Knowledge of prior drug levels did not modify the results. CONCLUSION: Systematic TDM at appointments following treatment failure showed similar results to TDM at visits without treatment failure. The prescribers' adherence with dosage recommendations was low in both cases. It is not clear whether better prescriber adherence would improve patient outcome. Furthermore, the ability to detect poor patient compliance is limited in a planned outpatient appointment. The study setting does not reflect on the general usefulness of TDM.

Dosing strategies of imipenem in neonates based on pharmacometric modelling and simulation.

OBJECTIVES: Imipenem is a broad-spectrum antibacterial agent used in critically ill neonates after failure of first-line treatments. Few studies have described imipenem disposition in this population. The objectives of our study were: (i) to characterize imipenem population pharmacokinetics (PK) in a cohort of neonates; and (ii) to conduct model-based simulations to evaluate the performance of six different dosing regimens aiming at optimizing PK target attainment. METHODS: A total of 173 plasma samples from 82 neonates were collected over 15 years at the Lausanne University Hospital, Switzerland. The majority of study subjects were preterm neonates with a median gestational age (GA) of 27 weeks (range: 24-41), a postnatal age (PNA) of 21 days (2-153) and a body weight (BW) of 1.16 kg (0.5-4.1). PK data were analysed using non-linear mixed-effect modelling (NONMEM). RESULTS: A one-compartment model best characterized imipenem disposition. Population PK parameters estimates of CL and volume of distribution were 0.21 L/h and 0.73 L, with an interpatient variability (CV%) of 20.1% on CL in a representative neonate (GA 27 weeks, PNA 21 days, BW 1.16 kg, serum creatinine, SCr 46.6 µmol/L). GA and PNA exhibited the greatest impact on PK parameters, followed by SCr. These covariates explained 36% and 15% of interindividual variability in CL, respectively.Simulated regimens using a dose of 20-25 mg/kg every 6-12 h according to postnatal age led to the highest PTA (T>MIC over 100% of time). CONCLUSIONS: Dosing adjustment according to BW, GA and PNA optimizes imipenem exposure in neonates.

Elevated acute phase proteins affect pharmacokinetics in COVID-19 trials: Lessons from the CounterCOVID - imatinib study.

This study aimed to determine whether published pharmacokinetic (PK) models can adequately predict the PK profile of imatinib in a new indication, such as coronavirus disease 2019 (COVID-19). Total (bound + unbound) and unbound imatinib plasma concentrations obtained from 134 patients with COVID-19 participating in the CounterCovid study and from an historical dataset of 20 patients with gastrointestinal stromal tumor (GIST) and 85 patients with chronic myeloid leukemia (CML) were compared. Total imatinib area under the concentration time curve (AUC), maximum concentration (Cmax ) and trough concentration (Ctrough ) were 2.32-fold (95% confidence interval [CI] 1.34-3.29), 2.31-fold (95% CI 1.33-3.29), and 2.32-fold (95% CI 1.11-3.53) lower, respectively, for patients with CML/GIST compared with patients with COVID-19, whereas unbound concentrations were comparable among groups. Inclusion of alpha1-acid glycoprotein (AAG) concentrations measured in patients with COVID-19 into a previously published model developed to predict free imatinib concentrations in patients with GIST using total imatinib and plasma AAG concentration measurements (AAG-PK-Model) gave an estimated mean (SD) prediction error (PE) of -20% (31%) for total and -7.0% (56%) for unbound concentrations. Further covariate modeling with this combined dataset showed that in addition to AAG; age, bodyweight, albumin, CRP, and intensive care unit admission were predictive of total imatinib oral clearance. In conclusion, high total and unaltered unbound concentrations of imatinib in COVID-19 compared to CML/GIST were a result of variability in acute phase proteins. This is a textbook example of how failure to take into account differences in plasma protein binding and the unbound fraction when interpreting PK of highly protein bound drugs, such as imatinib, could lead to selection of a dose with suboptimal efficacy in patients with COVID-19.