The pharmacokinetics of lorlatinib have been characterized in a population pharmacokinetic (PK) model by the license holder, but external validation with real-world data is lacking. As higher trough concentrations are linked to increased toxicity, there may be a role for model-informed precision dosing (MIPD). The published lorlatinib population PK model was externally validated using data from 150 patients with non-small cell lung cancer (NSCLC) treated in France and the Netherlands. Model performance was assessed using mean percentage error (MPE) and mean absolute percentage error (MAPE). Suboptimal validation results led to development of a refined population PK model, which was subsequently used to simulate lorlatinib exposure across different doses. A MIPD strategy targeting trough concentrations of 75–125 ng/mL was assessed. External validation revealed significant bias (MPE: −6.1
Marstacimab, a monoclonal antibody that targets tissue factor pathway inhibitor (TFPI), was developed for prophylactic treatment of hemophilia, with or without inhibitors. A nonlinear mixed-effects modeling approach was used to characterize plasma marstacimab and TFPI concentrations and identify covariates impacting marstacimab concentration. Population modeling using nonlinear mixed-effects modeling (NONMEM) 7.5.0 software was performed with marstacimab and total TFPI concentration data pooled from 213 participants across 6 clinical trials including healthy volunteers (n = 63) and participants with hemophilia (n = 150). Participants received subcutaneous marstacimab at doses ranging from 30 mg to 450 mg. Plasma samples to determine marstacimab and total TFPI were analyzed using validated assays. An Emax pharmacokinetic (PK)/pharmacodynamic (PD) model was developed to link model-predicted free TFPI concentrations to peak thrombin. Marstacimab and total TFPI concentrations were adequately described with a target mediated drug disposition (TMDD) model with nonlinear clearance. Body weight was the key structural covariate. After adjusting for body weight, no clinically relevant effect of age (adolescent vs adult), race (Asian vs non-Asian), participant status (healthy vs hemophilia) or mild hepatic impairment was seen. There was good agreement between observed and model-predicted peak thrombin levels in adults and adolescents, with no clinically relevant differences between the populations. A TMDD model with first-order absorption and quasi–steady-state approximation adequately characterized marstacimab PK and total TFPI concentrations. An Emax model adequately described the relationship between model-predicted free TFPI and peak thrombin. The PK/PD simulation indicated that no changes in dosing regimen based on age or body weight were warranted. ClinicalTrials.gov: NCT02531815, NCT02974855, NCT03363321, NCT03938792, NCT04832139, NCT04878731.
Tyrosine kinase inhibitors (TKIs) are targeted cancer therapies. However, TKIs are still limited due to their high inter-individual variability. This study evaluated target attainment using therapeutic drug monitoring (TDM) data from 12 TKIs, and investigated biochemical and patient-related characteristics influencing TKI pharmacokinetics (PK) This single-centre retrospective study included cancer patients treated with TKIs between January 2020 and August 2024. Demographic, clinical, and biochemical data were extracted from electronic health records. Univariate and multivariate linear mixed models were used to identify factors associated with TKI PK. A total of 1237 TKI concentrations from 309 patients were included. Target attainment percentages were: 74.6
Ulacamten (CK-4021586) is a small molecule allosteric inhibitor of cardiac myosin in development for treating heart failure with preserved ejection fraction. This first-in-human study evaluated safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and food effect (FE) of ulacamten in healthy adult participants. This was a phase I, double-blind, randomized, placebo-controlled, single and multiple ascending dose escalation (SAD, MAD) and FE study. Seven SAD cohorts (n = 10; eight active, two placebo) received oral doses of 10−600 mg, two MAD cohorts received 100 and 200 mg once daily for 7 days, and one FE cohort received a single 150-mg dose. Participants were required to have left ventricular ejection fraction (LVEF) ≥ 60
Therapeutic drug monitoring (TDM) and pharmacokinetic studies of beta-lactam antibiotics in critically ill patients aim to define optimal dosing and require accurate measurement of unbound drug concentrations. This study compared the performance of two ultrafiltration devices, Centrifree and Amicon, for measuring unbound concentrations of cefepime, meropenem, flucloxacillin, piperacillin and tazobactam. Non-specific binding (NSB) was specifically assessed in phosphate-buffered saline, and unbound concentrations were measured using a chromatographic method in both spiked plasma and plasma samples from critically ill patients, in order to compare the two ultrafiltration devices. Centrifree exhibited no significant NSB for any antibiotics (≤ 15
Rivoceranib, a vascular endothelial growth factor receptor-2 tyrosine kinase inhibitor with antitumor activity, is metabolized in the liver mostly by cytochrome P450 (CYP)3A4/5. In vitro studies suggest that rivoceranib at clinically relevant concentrations may inhibit metabolism of various CYP substrates. This study evaluated the effects of rivoceranib 200 mg once daily (QD) on the pharmacokinetics of various CYP substrates using the Cooperstown 5+1 cocktail. The dosing regimen of rivoceranib used in this study is similar to the proposed rivoceranib regimen (250 mg QD) in combination with camrelizumab for the treatment of patients with hepatocellular carcinoma. This open-label, fixed-sequence, crossover, drug–drug interaction phase I study evaluated the impact of multiple oral doses of rivoceranib 200 mg QD on the single oral dose pharmacokinetics of CYP enzyme substrates administered in the modified Cooperstown 5+1 cocktail (caffeine 200 mg [CYP1A2], warfarin 10 mg [S-warfarin as CYP2C9 substrate] + vitamin K 10 mg, omeprazole 40 mg [CYP2C19], dextromethorphan 30 mg [CYP2D6], and midazolam 2 mg [CYP3A4]) in 18 healthy volunteers. After fasting, volunteers received a single dose of the Cooperstown 5+1 cocktail on day 1 and rivoceranib plus Cooperstown 5+1 cocktail on day 11. After completing a meal, volunteers received a single dose of rivoceranib on days 6–10 and 12–15. Blood samples for pharmcokinetic analyses of substrates were collected pre-dose and up to 120 h post-Cooperstown 5+1 cocktail dosing on days 1 and 11. Volunteers returned once between days 21 and 25 for safety follow-up. Rivoceranib 200 mg QD decreased the cumulative area under the plasma concentration–time curve from time 0 to infinity (AUC0–inf) for caffeine by 20
Ocrelizumab (OCR) is an anti-CD20 monoclonal antibody approved for the treatment of relapsing-remitting multiple sclerosis (RRMS). Although the standard regimen consists of fixed 6-monthly infusions, therapeutic duration may vary between patients, highlighting the need for individualized dosing strategies. The objective of this study was to develop a pharmacokinetic-pharmacodynamic (PKPD) model able to predict patient-specific treatment responses, as a step towards a clinically applicable tool for optimizing OCR dosing precision in RRMS. Serum OCR concentrations and CD19⁺ lymphocyte counts from 11 treatment-naïve patients with newly diagnosed RRMS were analyzed. Samples were collected over 24 weeks following the first and second OCR infusions. Data were analyzed using a nonlinear mixed-effects population modelling approach in Monolix Suite 2023R1, with parameter estimation performed via the stochastic approximation expectation-maximization algorithm. Several structural models were evaluated, and model performance was assessed by fit statistics and visual predictive checks. The resultant two-compartment PKPD model successfully described OCR disposition and CD19⁺ lymphocyte depletion/repopulation. The final model included clearance of OCR without target-mediated elimination and described the effect of OCR on the dynamics of CD19⁺ lymphocyte counts. Simulations demonstrated the ability of the model to estimate the time to CD19⁺ lymphocyte repopulation and to explore optimal time for follow-up measurements. A novel PKPD model for OCR in RRMS that integrates drug exposure and CD19⁺ lymphocyte kinetics is presented. Although a small number of patients is included in the current study, this framework represents an important step toward clinically applicable, model-informed dosing strategies, with the potential to enhance treatment precision and support personalized therapy in RRMS. OVERLORD-MS: NCT04578639, ROS-MS: NCT06663111.
Interleukin (IL)-23p19 inhibitors are increasingly used in immune-mediated inflammatory diseases (IMIDs), particularly inflammatory bowel disease (IBD). Almost half of patients show inadequate response, partly due to pharmacokinetic (PK) variability. However, a comprehensive overview of their PK parameters is lacking, which limits understanding of population variability. This systematic review assessed the PK of IL-23p19 inhibitors in healthy subjects, IBD and other IMIDs. A systematic literature search was performed in PubMed/MEDLINE and Embase. Studies were screened by two independent researchers. Quality was assessed using the Cochrane risk of bias tool and the Clinical Pharmacokinetic Study Checklist. A total of 21 studies were included (risankizumab n = 9, guselkumab n = 6, tildrakizumab n = 3, mirikizumab n = 3), covering healthy subjects, psoriasis, psoriatic arthritis, Crohn’s disease (CD), ulcerative colitis (UC) and pustular/erythrodermic psoriasis. Only one study examined a distinct IBD group, specifically, mirikizumab in pediatric UC. For risankizumab, dose-normalized maximum concentrations and area under the concentration‑time curves over a dosing interval, along with central and peripheral volume of distribution and clearance were generally similar across CD and UC. Patients with CD and UC demonstrated increased risankizumab trough levels over consecutive dosing intervals, while an opposite trend was observed for other IMIDs. Covariate analysis revealed that only albumin in UC and body weight in CD were relevant covariates to risankizumab PK. Limited PK data and lack of subphenotype-specific data on IBD highlight the need for future studies to better define PK parameters. Also, more research is needed to guide personalized dosing strategies for IL-23p19 inhibitor use in IBD, as well as in other IMIDs. Doctors can prescribe biologics to patients diagnosed with autoimmune disease. Not all patients respond to biologic therapy in the same way. In part, this is caused by their bodies processing the biologics differently. Therefore, it is important to study how biologics are processed by the human body. A new class of biologics, called IL-23p19 inhibitors, have already shown promising treatment results for patients with psoriasis and those with inflammatory bowel disease (IBD). Unfortunately, differences in treatment responses among patients are observed, making it difficult for doctors to know whether the treatment would be successful for their patients. In order to provide doctors with more insights in this topic, this study summarized all the current knowledge on ways in which IL-23p19 inhibitors are processed by the bodies of patients with autoimmune disorders, with a specific focus on patients with IBD. Our findings show that only limited research has been done for patients with IBD. Even less attention has been given to specific IBD subtypes. For example, research is scarce with regard to patients with Crohn’s disease who experience frequent perianal disease activity and fistulas. We also highlight the importance of personalized treatment and show how our study can help guide it. Understanding how IL-23p19 inhibitors are processed by the body can help doctors choose the best dose and time for each patient. This leads to treatments that are better tailored to the needs of specific patients, resulting in better treatment outcomes and increased quality of life for patients living with autoimmune diseases.
Simultaneous pancreas kidney transplantation (SPK) is a preferred option for type 1 diabetes (T1DM) patients with end-stage renal disease (ESRD). Most transplant centers use kidney transplant (KT) protocols target trough concentrations (C0) to dose tacrolimus in SPK recipients, due to a lack of evidence for optimal tacrolimus C0 in SPK recipients. However, tacrolimus pharmacokinetics (PK) might be altered in SPK recipients due to diabetic gastroparesis or complications from intraperitoneal surgery and/or enteric drainage. We therefore aimed to compare oral tacrolimus PK in SPK versus KT recipients as a first step to define the optimal target tacrolimus concentrations in SPK recipients. A retrospective observational study was performed to describe and compare tacrolimus population PK in SPK and KT recipients. Relevant demographic and PK data were extracted from our local transplantation database for patients transplanted between 2005 and 2020 at our hospital. Pharmacokinetic data were analyzed using nonlinear mixed effect modeling in NONMEM. Furthermore, simulations were performed to assess potential differences in AUC0-12h to C0 ratios between SPK and KT recipients. Tacrolimus population PK in SPK and KT recipients were best described by two-compartmental models. The combined SPK and KT model showed a significantly reduced oral absorption rate for SPK recipients, compared to KT recipients (0.231 h−1 vs 0.336 h−1 respectively). Simulations indicated a 10
Immunosuppressed patients are susceptible to serious viral infections, often necessitating antiviral prophylaxis and/or treatment. Therapeutic drug monitoring (TDM) has been proposed to optimise drug exposure and clinical outcomes and is typically performed on full blood/plasma samples. Saliva offers a less invasive, patient-friendly approach, and this systematic review aims to assess the feasibility of saliva-based assays for antiviral TDM. We conducted a search on MEDLINE, EMBASE and ClinicalTrials.gov databases, governmental regulatory websites and conference abstracts. Primary studies reporting both saliva and plasma concentrations of antivirals used forprophylaxis or treatment of opportunistic viral infections were included. Physicochemical properties of eachantiviral were compiled from PubChem and DrugBank to predict salivary excretion. Feasibility classifications were defined as follows: (1) likely, (2) possible, (3) unlikely, (4) unclear but possible, (5) unclear but unlikely. We included nine studies in our review. (Val)acyclovir and favipiravir were considered possibly feasible for saliva-based TDM, whereas molnupiravir and oseltamivir were unclear but possible. Nirmatrelvir was deemed unclear but unlikely. For other included antivirals, no primary studies were available, however, physicochemical profiles suggest that salivary penetration may be feasible for some agents but limited for others. Studies documenting both saliva and plasma concentrations were scarce, and data was inconsistent. Findings from clinical studies sometimes contradicted predictions of penetration based on drug properties, suggesting that other factors, such as drug transporters, may significantly influence the salivary excretion of antivirals. Future robust, standardised investigations are required to confirm the clinical utility of saliva-based TDM. Feasibility is therefore currently inconclusive, but preliminary evidence is promising.
Epcoritamab is approved for treating various relapsed/refractory (R/R) lymphomas. In a phase I/II study in R/R follicular lymphoma (FL) patients, epcoritamab demonstrated high response rates (EPCORE NHL-1: objective response rate [ORR]: 82.0
Personalizing anti-tumor necrosis factor (TNF) therapy in pediatric Crohn’s disease (CD) remains challenging due to variable drug clearance and response. Identifying pharmacokinetic (PK) and pharmacodynamic (PD) predictors of deep remission could enable precision dosing strategies. The primary aim was to define PK metrics and PD biomarkers associated with deep remission. Patients initiating infliximab or adalimumab were prospectively enrolled from four pediatric centers with longitudinal blood and stool biospecimens collected for one year. Deep remission was defined as a combination of weighted pediatric CD activity index (wPCDAI) < 12.5 and Simple Endoscopic Score-CD < 3. Trough concentrations (cTrough) were measured throughout the study. Drug exposure (area under the curve, AUC) and clearance were estimated using drug-specific population PK models and Bayesian estimation using nonlinear mixed-effects modeling (NONMEM). Deep remission was achieved in 34/70 (48.6
Tacrolimus therapeutic drug monitoring after kidney transplantation is primarily guided by the pre-dose concentration (C0), assuming it reflects overall drug exposure. At the same time, the tacrolimus concentration-to-dose ratio (C0/dose) has emerged as a marker associated with clinical outcomes after transplantation, suggesting that differences in peak (maximum concentration [Cmax]) and total tacrolimus exposure (area under the concentration–time curve from 0 to 24 h [AUC0–24h]) may not be fully captured by C0 alone. In 534 kidney transplant recipients followed for up to 13 months post-transplantation, 635 tacrolimus pharmacokinetic profiles with corresponding C0 values were analyzed. The C0/dose category was defined using the C0/dose ratio and classified as fast (<1.05 ng·mL⁻1·mg⁻1, n = 344), intermediate (1.05–1.53, n = 127), or slow (≥1.54, n = 164). Analyses were restricted to measurements with C0 between 5.0 and 6.0 ng/mL to compare Cmax and AUC0–24h across C0/dose categories and tacrolimus formulations (immediate release vs extended release) using linear mixed-effects models. Sensitivity analyses evaluated C0-adjusted Cmax and AUC0–24h in the full cohort (4271 pharmacokinetic profiles) and assessed consistency when Cmax was predicted using population pharmacokinetic models. Despite comparable C0 levels, the fast C0/dose category was associated with substantially higher tacrolimus doses and had higher peak concentration and total exposure. Under immediate-release tacrolimus, Cmax and AUC0–24h were 30 and 18
Tacrolimus is a narrow therapeutic index drug with wide intrapatient and interpatient pharmacokinetic variability and cytochrome P450 3A5 (CYP3A5) genotype-guided dosing recommendations. This review aimed to evaluate population pharmacokinetic models and dosing algorithms across all treatment settings that analyzed the influence of CYP3A5 genotypic variation plus additional clinical covariates on tacrolimus pharmacokinetics. These effects were mathematically translated and summarized to provide a comparison between models. Changes in apparent clearance warranting tacrolimus dose adjustments were assessed and summarized by relative magnitude and direction. Sixty-eight tacrolimus population pharmacokinetic models were included in this review, including 55 developed for adults and 38 for kidney transplant recipients. The most frequently retained covariates on tacrolimus clearance were CYP3A5 genotype (88
Intravenous (IV) infusion remains the predominant delivery route for oncology monoclonal antibodies, but it requires prolonged chair time and substantial infusion-unit resources. Hyaluronidase-facilitated subcutaneous (SC) formulations aim to shorten administration (minutes vs hours), improve convenience, and potentially expand outpatient or home-based delivery, while preserving exposure, efficacy, and safety. We conducted a narrative review of published clinical studies, major congress presentations, trial registries, and Food and Drug Administration (FDA)/European Medicines Agency (EMA) regulatory documents describing development of hyaluronidase-facilitated SC formulations for seven oncology antibodies (trastuzumab, rituximab, daratumumab, atezolizumab, nivolumab, pembrolizumab, and amivantamab). We extracted evidence on formulation strategy, pharmacokinetic (PK) bridging, efficacy comparability, safety/immunogenicity, and regulatory pathways supporting IV→SC approval. Across programs, PH20-based recombinant hyaluronidases, including human hyaluronidase PH20 (rHuPH20) and berahyaluronidase alfa, transiently depolymerize SC hyaluronan, enabling delivery of multi-milliliter injections and high fixed doses. Development strategies converged on PK-anchored bridging, typically targeting non-inferior SC/IV geometric-mean ratios for both initiation and maintenance exposure (e.g., cycle-1 area under the curve [AUC]/average plasma concentration [Cavg] and minimum plasma concentration [Cmin]/trough concentration [Ctrough]), supported by population PK to ensure covariate coverage. We highlight a pragmatic evolution in trial design: earlier conversions often paired PK with direct clinical activity confirmation in sensitive settings, whereas more recent programs increasingly use prespecified PK non-inferiority as the confirmatory backbone with efficacy as supportive reassurance—enabling use of an approved SC formulation across multiple indications. In pivotal bridging trials, SC regimens generally met or exceeded exposure targets and demonstrated efficacy consistent with IV comparators (treatment effects clustering around unity; Δ ≈ 0; hazard ratio/relative risk ≈ 1). Safety profiles were broadly similar; SC administration was associated with fewer administration-related reactions for several agents, while injection-site reactions were usually mild. Immunogenicity, including anti-hyaluronidase antibodies, did not show consistent clinically meaningful effects on PK or outcomes. Hyaluronidase-facilitated IV→SC conversion has become a reproducible, model-informed, PK-driven development paradigm. By synthesizing study-design choices, formulation pathways, and extrapolation logic across seven approved antibodies—including the recent IO and targeted-therapy wave—this review builds upon a previously described clinical bridging concept and provides a comprehensive updated overview including the most recently approved products, with a practical framework to guide future IV→SC transitions in oncology.
Dolutegravir-based regimens are part of the preferred regimens in all populations living with HIV, but dolutegravir’s pharmacokinetics can vary greatly with factors such as drug–drug interactions (DDIs) and age. For example, DDIs between dolutegravir and rifamycins in countries with a high burden of HIV/tuberculosis co-infection present a major challenge. Attaining therapeutic concentrations is crucial for virologic success and to prevent resistance. Understanding dolutegravir pharmacokinetics and its sources of variability is essential to ensure adequate exposure in all individuals. Population pharmacokinetic (PopPK) modeling is a powerful tool for characterizing medication disposition. In this review, we aim to synthesize existing dolutegravir PopPK models, highlighting key pharmacokinetic parameters and covariate effects. A literature search was done on Medline and Embase databases from inception to November 18th, 2025. This review included 23 studies: 15 in adults, 4 in pediatrics, 2 in pregnancy (mothers and their newborn), and 2 in term neonates. Almost all models included allometric scaling, with body weight especially, on apparent clearance (CL/F) and/or apparent volume of distribution (Vd/F) parameters. When considering differences in body size, CL/F and Vd/F were similar across populations. The absorption rate constant (ka) was higher in adults and presented high variability across populations. Other common covariates in adults and pediatrics were co-medications and background antiretrovirals. Data and tested covariates were limited in pregnant women and neonates. Study simulations and predefined target values indicated adequate recommended dolutegravir doses. Further characterization of dolutegravir PopPK in populations at risk of altered concentrations (e.g., preterm neonates, pediatrics, pregnancy, obesity, and older adults) is crucial to better understand dolutegravir pharmacokinetics in these populations as data are still limited.
Bioequivalence studies are important for a generic drug to enter the market. These studies mainly examine various pharmacokinetic parameters like Cmax, AUC0–T and AUC0–∞. But at times, these parameters might not be sufficient to pick up essential kinetics. It is even possible to undertake the additional parameter along with the traditional pharmacometrics. This article gives an overview of one such parameter, partial area under the curve (pAUC), which captures specific time intervals of clinical relevance. The pAUC is especially useful for comparing specific formulations, determining bioequivalence in early or late stages, and assessing medicines with time-dependent therapeutic windows. When employed correctly, pAUC improves our understanding of temporal drug behaviour beyond what total AUC can provide, allowing for more precise and clinically meaningful pharmacokinetic assessments. This article is a review that describes how pAUC has been used in specific regulatory guidelines for drug products that have time-dependent exposures, which may impact the drug’s pharmacodynamic properties. These product guidances have been issued by the US Food and Drug Administration (FDA), Health Canada, and European Medicines Agency (EMA). This article presents various viewpoints about pAUC in the mindset of regulators, researchers, and industrial experts.
Understanding intrapulmonary pharmacokinetics (PK) following inhalation remains a significant challenge in drug development and repurposing. Current lung sampling methods include bronchoalveolar lavage (BAL), biopsies, and the more recent bronchosorption technique, which enhances regional specificity while reducing potential quantification errors. This study aimed to develop a pulmonary population physiologically based pharmacokinetic (PBPK) model for inhaled salbutamol by integrating data from all three sampling techniques to improve PK predictions and to compare different sampling strategies to optimize future study designs. A population-based minimal PBPK model was developed using data from a previously published study (NCT03524066) investigating salbutamol's pulmonary and plasma PK in 13 healthy volunteers after inhalation. Simulations assessed the impact of permeability on pulmonary PK profiles and BAL-derived epithelial lining fluid (ELF)-to-plasma ratios using salbutamol as a reference compound. Stochastic simulation-estimation (SSE) methods were employed to assess the feasibility of different sampling strategies for estimating key parameters of the PBPK model. First, we evaluated using one or two sampling techniques within a single bronchoscopy session. Second, we compared uniform and staggered bronchosorption-based sampling strategies for drugs from different permeability categories. The minimal PBPK model described pulmonary PK of salbutamol across the lung and estimated the unbound tissue–plasma partition coefficient for the lung ( K_p,u,lung ) and the effective permeability ( P_eff ) of salbutamol as 11.0 and 0.543 m/h, respectively. Inter-individual variabilities (IIV) were found on plasma clearance and lung deposition fraction. No significant IIV was detected on K_p,u,lung or P_eff . Simulations indicated that low-permeability drugs exhibited higher concentrations in the ELF, while high-permeability drugs accumulated more in lung tissues, after inhalation. Results from SSE showed that bronchosorption plus biopsy were the most informative two-technique combination and bronchosorption alone was the best single-technique option. Additionally, the optimal sampling strategy for both uniform and staggered sampling depended on drug permeability, with early time points favoured for high-permeability drugs and later or broader windows needed for low-permeability drugs. A pulmonary population PBPK model for inhaled salbutamol was developed by integrating detailed intrapulmonary data from bronchoalveolar lavage, biopsy, and bronchosorption. The study revealed that parameter estimates of K_p,u,lung and P_eff were sensitive to the sampling technique. Staggered sampling strategies mitigated the risk of biased estimates, though the ideal sampling windows varied by drug’s permeability. These findings support model-informed, permeability-driven study design in inhaled drug development.
The pharmacokinetic profiles of methylprednisolone (MP) in plasma and urine were evaluated after single and multiple oral doses. MP is prohibited in sports competitions when administered systemically (oral, injectable, or rectal administrations) whereas other routes remain permitted for therapeutic purposes. The aim of this study was to characterize the urinary MP excretion after oral administration to assess whether the current World Anti-Doping Agency minimum reporting level of 30 ng/mL in urine is appropriate for distinguishing permitted from prohibited administrations, as well as whether the recommended washout period is adequate. Another aim was to better define MP elimination kinetics and evaluate its systemic effects. Sixteen healthy male participants were enrolled and divided into two groups. One group received a single oral dose of 12 mg of MP, while the other received 12 mg daily for 3 consecutive days. Urine and blood samples were collected before, during, and after administration. Urine samples were analyzed for MP and 15 metabolites using a sensitive and selective liquid chromatography-tandem mass spectrometry method. Plasma samples were analyzed for unchanged MP and cortisol using liquid chromatography-tandem mass spectrometry. A pharmacokinetic analysis was performed using a one-compartment model with first-order absorption, combining plasma concentrations and urinary excretion data. MP represented only a small proportion of the administered dose, confirming that metabolism is the main elimination pathway. After a single oral dose, urinary MP concentrations above 30 ng/mL were observed up to 12 h, while all samples collected later were below this concentration. After multiple dosing, most samples above 30 ng/mL were also found within 12 h, although a few participants still showed concentrations above the minimum reporting level in the 12 to 24 h period. All samples collected more than 24 h after the last dose were below 30 ng/mL. In plasma, MP reached peak concentrations around 1.6–2.3 h after administration and was not detectable 24 h after the last dose. Cortisol concentrations were markedly suppressed after dosing, with recovery to baseline within 24–48 h depending on the regimen. This study confirms that the current urinary minimum reporting level of 30 ng/mL is appropriate for detecting oral MP use while minimizing the risk of false adverse analytical findings. The results also support the adequacy of the current 3-day washout period. Modern liquid chromatography-tandem mass spectrometry analysis and combined plasma-urine pharmacokinetic modeling provided robust evidence that MP is rapidly eliminated, extensively metabolized, and associated with transient cortisol suppression after oral administration. EudraCT number 2020-004596-41.
