European Journal of Drug Metabolism and Pharmacokinetics最新文献

Background and objectives: Cannabis consumption is increasing in both the recreational and medical settings. Tetrahydrocannabinol (THC) is known to produce cardiovascular effects, but the specific roles of THC and its metabolites THC-OH and THC-COOH in cannabinoid-induced cardiovascular effects remain unclear. We hypothesized that THC and THC-OH mediate a cannabinoid-induced increase in heart rate in either an additive or synergistic fashion.

Methods: The present study uses prospectively obtained data to evaluate the effect of THC and its metabolites on heart rate in healthy volunteers through non-linear mixed-effect pharmacokinetic/pharmacodynamic (PK/PD) modeling.

Results: The PK/PD models reveal that THC, THC-OH and a combination of THC and THC-OH, but not THC-COOH, are responsible for THC-induced tachycardia. The EC50 of the THC Emax model was 0.53 µM, 25-fold the EC50 for the THC-OH Emax model. The General Empiric Dynamic Model indicates that THC and THC-OH act synergistically to increase heart rate. Neither sex nor CYP2C9 polymorphism contributes to THC-induced tachycardia.

Conclusion: THC-OH but not THC-COOH contributes to the heart rate effect of THC and THC-OH may be acting in a synergistic manner with THC. This contributes to understanding the cardiovascular effects of THC and cannabis-induced cardiovascular events. Future research including further hemodynamic data will allow a detailed systems pharmacology or response surface model approach.

Trial registration: www.isrctn.com ; registration number ISRCTN53019164.

Background and objectives: Recaticimab (SHR-1209) is a humanized monoclonal antibody that binds to the proprotein convertase subtilisin/kexin type 9 (PCSK9) with high affinity. This study was conducted to compare the relative bioavailability, pharmacokinetics (PK), pharmacodynamics (PD), and safety of recaticimab following subcutaneous injection at three different sites in healthy Chinese subjects.

Methods: In this randomized, parallel, open-label, phase I study, 159 healthy Chinese subjects were randomized to receive a single dose of 450 mg recaticimab subcutaneously into the abdomen, upper-arm, or thigh and were followed up until 113 days postdose. Adverse events were monitored, and serum samples were collected for PK, PD, and immunogenicity evaluation during the study.

Results: The PK profiles of recaticimab were similar among different injection site groups. The geometric mean ratios of maximum serum concentration (C_max), area under the serum concentration versus time curve (AUC) from time zero to the time of last quantifiable concentration (AUC_0-last), and AUC from time zero extrapolated to infinity (AUC_0-inf) between groups were all close to 1, with two-sided 90% confidence intervals within 0.8-1.25. Recaticimab showed similar effects on low-density lipoprotein cholesterol levels in all groups, with mean maximum percentage decreases ranging from 56.88% to 59.04%. The percentage changes from baseline in free PCSK9 and other lipid variables were similar across the three groups as well. Treatment-emergent adverse events were reported in 41/53 (77.4%, abdomen), 29/53 (54.7%, upper-arm), and 42/53 (79.2%, thigh) subjects, most of which were mild and resolved without treatment. The incidence of antidrug antibodies among the three groups was comparable.

Conclusions: A single subcutaneous injection of 450 mg recaticimab into the abdomen, upper-arm, or thigh was well-tolerated and presented similar PK and PD profiles, which supported the interchangeable use of the three injection sites for patients.

Clinical trial identifier: ( www.

Clinicaltrials: gov ) NCT05370950 2022-05-07.

Background and objectives: Doxorubicin (DOX) and its metabolite doxorubicinol (DOXol) are drugs with large differences in pharmacokinetics (PK) between patients. In this study, we investigated the effects of polymorphisms in PK-related genes on the areas under the plasma concentration-time curves (AUCs) of DOX and DOXol.

Methods: This study included 43 patients diagnosed with non-Hodgkin lymphoma undergoing the first round of CHOP therapy. The AUCs of DOX and DOXol were calculated using the linear trapezoidal rule based on the plasma concentrations in blood sampled from 1.5 to 25.5 h after the start of administration. Genotyping was performed for genes encoding carbonyl reductase (CBR1, CBR3), aldo-keto reductase (AKR1C3), and transporters (ABCB1, ABCG2).

Results: Although the dose of DOX was adjusted for body surface area for each patient, the coefficients of variation for the AUCs of DOX and DOXol were substantial. Serum albumin was identified as an independent factor significantly influencing the dose-adjusted AUC of DOX (AUC/D; R² = 0.116, P = 0.015). Additionally, body mass index was identified as an independent factor significantly influencing the AUC/D of DOXol and the DOX-DOXol AUC ratio (DOXol/DOX; R² = 0.181, P = 0.003 and R² = 0.134, P = 0.009, respectively). Nonetheless, no significant differences in PK parameters were observed among polymorphisms in PK-related genes.

Conclusions: Our findings suggested that polymorphisms in CBR1, CBR3, AKR1C3, ABCB1, and ABCG2 were unlikely to be reliable predictors of cumulative plasma exposure to DOX and DOXol. Therefore, mitigating the risk of cumulative plasma exposure to DOX and DOXol through PK approaches may require the development of novel therapeutic drug monitoring strategies. Supplementary file1 (MP4 3804 KB).

The clinical pharmacology of antiretroviral therapy (ART) in critical care presents unique challenges due to the complex interplay between HIV infection, critical illness, and drug management. This comprehensive review examines the pharmacokinetic and pharmacodynamic considerations of antiretroviral drugs in critically ill patients, where altered absorption, distribution, metabolism, and excretion significantly impact drug effectiveness and safety. Critical illness can substantially modify drug pharmacokinetics through various mechanisms, including impaired gastrointestinal motility, fluid shifts, hypoalbuminemia, hepatic dysfunction, and altered renal function. These changes, combined with potential drug-drug interactions in the polypharmacy environment of intensive care units, necessitate careful consideration of dosing strategies and monitoring approaches. The review addresses specific challenges in various critical care scenarios, including management of ART in patients with organ dysfunction, during renal replacement therapy, and in special populations such as those with sepsis or acute respiratory distress syndrome. It also explores the role of therapeutic drug monitoring in optimizing antiretroviral therapy and managing drug toxicities in critical care settings. Emerging areas of research, including long-acting formulations, nanotechnology-based drug delivery systems, and personalized medicine approaches, are discussed as potential future directions for improving ART management in critical care. The review emphasizes the importance of a multidisciplinary approach involving critical care physicians, infectious disease specialists, and clinical pharmacists to optimize outcomes in this complex patient population. This review provides clinicians with practical guidance for managing ART in critically ill patients while highlighting areas requiring further research to enhance our understanding and improve patient care in this challenging setting.

Background and objective: A gonadotropin-releasing hormone (GnRH) agonist such as leuprolide is widely used to achieve sustained suppression of testosterone levels, which play a critical role in the treatment of prostate cancer. Recent advances in drug delivery systems have led to the development of long-acting depot formulations, such as the 6-month intramuscular (IM) leuprolide formulation, which aim to simplify dosing and improve convenience for both patients and healthcare providers. Exploring extended dosing intervals for such formulations represents a promising approach to further optimize treatment regimens, potentially balancing efficacy with patient-centered care. The objective was to evaluate the efficacy of various extended dosing regimens of the leuprolide 6-month IM depot formulation for prostate cancer treatment. The primary objective was to assess whether extended dosing intervals could maintain testosterone concentrations below the castrate threshold of < 0.5 ng/ml and < 0.2 ng/ml in over 90% of subjects, as outlined in regulatory criteria.

Methods: The study utilized a previously published pharmacokinetic/pharmacodynamic model to simulate the testosterone suppression profiles for different extended dosing regimens, including every 6 months (Q6M), 7 months (Q7M), 8 months (Q8M), 9 months (Q9M), 10 months (Q10M), 11 months (Q11M), and 12 months (Q12M). The simulations were carried out with 1000 virtual subjects. Sensitivity analyses were also conducted to account for variability in baseline testosterone levels and fraction of drug absorbed.

Results: The simulation results indicated that extending the dosing interval from Q6M to Q8M could ensure that over 90% of subjects maintain testosterone concentrations below 0.2 ng/ml. Similarly, extending the dosing interval to Q9M would keep testosterone concentrations below 0.5 ng/ml in over 90% of subjects. The sensitivity analyses confirmed that these extended dosing regimens consistently achieved and maintained target testosterone levels across various scenarios.

Conclusion: The findings support the feasibility of extending the dosing intervals for the leuprolide 6-month IM depot formulation beyond the label-recommended 6 months. Specifically, the Q8M and Q9M regimens emerged as viable candidates for further clinical evaluation, offering potential benefits in reducing injection frequency while maintaining therapeutic efficacy. Further clinical studies are necessary to confirm the long-term efficacy of these extended dosing regimens.

Background and objective: Total glucosides of paeony (TGP) capsules, tripterygium glycoside tablets (TGT), and celecoxib are commonly used drugs in clinical practice for the treatment of Rheumatoid arthritis (RA). An UPLC-MS/MS method for the analysis of celecoxib in beagle dogs was developed, the herb-drug interactions (HDIs) between TGP and TGT with celecoxib were studied based on pharmacokinetics.

Methods: The method of acetonitrile precipitation was applied to process plasma samples. Celecoxib and furosemide (internal standard, IS) was separated by gradient elution, and detected using multiple reaction monitoring mode under the positive ion. The ion reactions used for quantitative analysis were m/z 379.82 → 315.82 for celecoxib, and m/z 328.74 → 204.88 for IS. HDIs experiments adopt a three-stage experimental design. In the first period, six beagle dogs was orally administered 6.67 mg/kg celecoxib. In the second period, TGP 20 mg/kg was given orally twice a day for 7 consecutive days, then celecoxib was orally administered. And, in the third period, TGT 1.5 mg/kg was orally given, twice a day for 7 consecutive days, then celecoxib was orally administered. The concentration of celecoxib in the three periods was detected, and HDIs were evaluated based on pharmacokinetics.

Results: Celecoxib exhibited good linearity in the range of 10-2000 ng/mL. The accuracy, precision, recoveries, matrix effects, and stability all met the standards. When celecoxib was used in combination with TGPC or TGT, the main pharmacokinetic parameters of celecoxib changed, C_max, AUC_(0-t) and AUC_(0-∞) increased, t_½ was prolonged, and CL and V_d decreased.

Conclusion: A novel UPLC-MS/MS approach was successfully performed and applied to measure celecoxib in beagle dog plasma. TGP and TGT could inhibit the metabolism of celecoxib in beagle dogs, thereby affecting the pharmacokinetic parameters of celecoxib and increasing plasma exposure to celecoxib.

Objective: The objective of this study was to determine the apparent intrinsic clearance (Cl_{int, app}) and fraction unbound in human liver microsomes (f_{u, mic}) of 86 marketed central nervous system (CNS) drugs and to predict the in vivo hepatic blood clearance (CL_{h, b}).

Methods: Cl_{int, app} in human liver microsomes (HLM) was determined by substrate depletion, and f_{u, mic} was determined by equilibrium dialysis. The relationship between lipophilicity (logP) and unbound intrinsic clearance (Cl_{int, u}) was explored using the Biopharmaceutical Drug Disposition Classification System (BDDCS) and Extended Clearance Classification System (ECCS). The predicted hepatic blood clearance by direct scaling, conventional method and Poulin method using well-stirred (WS) and parallel-tube (PT) models were compared with observed values.

Results: The Cl_{int, app} in HLM ranged from < 5.8 to 477 µl/min/mg. The f_{u, mic} in HLM ranged from 0.02 to 1.0. The scaled Cl_int values ranged from < 5 to 4496 ml/min/kg. The metabolic rate increased with an increase in logP (logP ≥ 2.5) of the CNS compounds. The direct scaling and Poulin methods showed comparable results based on the percentage of clearance predictions within a two-fold error. The conventional method resulted in under-predictions of Cl_{int, in vivo} or CL_{h, b} using the WS or PT models. The Poulin method is favored over the other methods based on the statistical parameters.

Conclusions: Experimental Cl_{int, app} and f_{u, mic} for 86 CNS compounds were successfully determined, and the scaled clearance was used to predict the hepatic blood clearance of 34 drugs. The success of prospective clearance predictions using HLM is expected to be high for most of the lipophilic BDDCS class 1 and class 2 and ECCS class 2 CNS compounds. The Poulin method resulted in more accurate predictions falling within a two-fold error of the observed values using the WS or PT models.

Background and objective: Atorvastatin is dosed in its active acid form although it exists in equilibrium with its inactive lactone form in vivo. Although in vitro atorvastatin acid displays pH-dependent conversion to the lactone metabolite, pharmacokinetic (PK) data on the effect of elevated gastric pH on atorvastatin and major atorvastatin-related species are not currently available. In this dedicated study, we investigated the effect of food and acid-reducing agents on the PK of atorvastatin and its three major metabolites in humans.

Methods: This was an open label, randomized, crossover study conducted in 17 healthy volunteers. Part 1 examined the PK of a 10-mg dose of atorvastatin co-administered with or without a 600-mg dose of sodium bicarbonate in fasted and fed states. Part 2 was a single assessment to examine the PK of a 10-mg dose of atorvastatin in the fasted state following a 5-day treatment course of 40-mg daily esomeprazole. Gastric pH was monitored during treatments using Heidelberg capsules. A linear mixed effects model was used to derive ratios for PK parameters of atorvastatin and metabolites between treatments.

Results: Similar to previous food effect studies, food significantly decreased the maximum concentration (C_max) and increased the time to C_max (t_max) of atorvastatin, with minimal effect on total exposure of atorvastatin or metabolites. Neither sodium bicarbonate, in the fed or fasted state, nor treatment with esomeprazole had a clinically meaningful effect on the exposure of atorvastatin or its metabolites.

Conclusions: According to these results, atorvastatin PK does not appear to be sensitive to changes in gastric pH.

Background and objectives: As an immunosuppressant, mycophenolate mofetil (MMF) is used to prevent graft versus host disease (GVHD) in patients after hematopoietic stem cell transplantation (HCT). This study aimed to establish a population pharmacokinetic model and simulate the dosage protocol in HCT patients with thalassemia (TM) to fill the gap of lacking MMF dosing regimen.

Methods: The mycophenolic acid (MPA) plasma concentrations were obtained from HCT patients with TM after using MMF. The population pharmacokinetic (PPK) parameters were obtained by NONMEM (Version VII, Level 2.0; ICON Development Solutions, Ellicott City, MD, USA) program. Monte Carlo simulations were used to determine the optimal dosing.

Results: A total of 239 blood samples from 31 pediatric patients were available, the PPK of MPA was described as a two-compartment model. The typical values for MPA clearance (CL), central distribution volume (V₂), peripheral distribution volume (V₃), intercompartmental clearance (Q), and absorption rate constant (Ka) were 14.9 L/h, 83.5L, 141L, 3.13 L/h, and 1.37/h respectively. The inter-individual variability (IIV) of CL and V₂ were 35% and 41%, respectively. Simulation results suggested that, as the patient's body surface area (BSA) value increased, MMF dosage initiated from 500 mg twice daily was effective.

Conclusions: A 'tiered' dosage regimen including patient urea and with doses stratified across BSA quartiles, rather than a 'one dose fits all' regimen, would help individualize MMF therapy in this population.