Pharmacokinetic Modeling of Morphine's Effect on Plasma Concentrations of Ticagrelor and Its Metabolite in Healthy Volunteers.
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SUBMITTER: Buszko K
PROVIDER: S-EPMC8264498 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Background and objectiveWomen with postpartum depression (PPD) may expose their infants to antidepressants via breast milk. Brexanolone is the only FDA-approved antidepressant specifically indicated for the treatment of PPD. This open-label, phase Ib study of healthy lactating volunteers assessed pharmacokinetic (PK) properties of brexanolone and a population PK (PopPK) model determined the relative infant dose (RID) in breastfeeding mothers.MethodsTwelve participants received a 60-h infusion of brexanolone (titration up to 90 µg/kg/h). Allopregnanolone concentration was measured in breast milk and plasma. The RID was computed using a nonlinear mixed-effects PopPK model of patients with PPD and healthy women (N = 156). Model results were extended across an integrated dataset of participants through day 7.ResultsAllopregnanolone concentration-time profiles were similar between breast milk and plasma (partition coefficient for concentration gradient [milk : plasma] 1.36). Mean (95% CI) Cmax was 89.7 ng/mL (74.19-108.39), and median (95% CI) tmax was 47.8 h (47.8-55.8) in plasma. The overall PK profile was best described by a two-compartment model with linear elimination and distribution. Body weight was the only significant covariate identified. There were no apparent differences in PopPK AUC and Cmax between participants with or without concomitant antidepressant treatment. Maximum RID was 1.3%.ConclusionThe PopPK model successfully described the variability and concentration-time profiles of allopregnanolone in breast milk and plasma in healthy participants and in the plasma of brexanolone-treated patients with PPD. The rapid elimination of allopregnanolone from plasma and breast milk, and low RID, suggests the appropriateness of brexanolone weight-based dosing and supports other PK-related labeling recommendations.
| S-EPMC9439988 | biostudies-literature
Project description:PB2452, a neutralizing monoclonal antibody fragment that binds the antiplatelet drug ticagrelor with high affinity, is being developed as a ticagrelor reversal agent. To identify a clinically useful intravenous (i.v.) reversal regimen, a semimechanistic exposure-response model was developed during the PB2452 first-in-human phase I study. From a randomized, double-blind, placebo-controlled, single-dose trial to evaluate the safety, efficacy, and pharmacokinetics (PKs) of PB2452 in 61 healthy volunteers pretreated with ticagrelor, sequential dose cohort data were used to build and refine an exposure-response model that combined population PK models for ticagrelor (TICA), ticagrelor active metabolite (TAM), and PB2452, and related their binding relationships to the PK of uncomplexed TICA and TAM which is predictive of platelet inhibition. Platelet function was assessed by multiple assays. The model was developed using Bayesian methods in NONMEM. Human PK and pharmacodynamic data from sequential dose cohorts were used to initially define and then refine model parameters. Model simulations indicated that an initial i.v. bolus of PB2452, followed by a high-rate infusion, and then a slower-rate infusion would provide immediate and sustained reversal of the antiplatelet effects of ticagrelor. Based on model predictions, a 6 g i.v. bolus followed by 6 g infused over 4 h and then 6 g over 12 h was identified and tested in study subjects and shown to provide complete reversal within 5 min of infusion onset that was sustained for 20-24 h. The model is predictive of the reversal profile of PB2452 and will inform future trials of PB2452.
| S-EPMC8752111 | biostudies-literature
Project description:Background: Ticagrelor belongs to a new class of P2Y12 receptor inhibitor that has been widely used for antiplatelet therapy. This study aimed to explore the effect of single nucleotide polymorphisms (SNPs) in metabolic enzymes, transporters, and other relevant variants on the pharmacokinetics (PK) of ticagrelor and its active metabolite, AR-C124910XX. Methods: The study population comprised 68 healthy Chinese volunteers who were enrolled in a ticagrelor bioequivalence clinical trial. The PK profile of ticagrelor was evaluated after orally administering a single 90-mg dose of ticagrelor in tablet form. The plasma concentrations of ticagrelor and AR-C124910XX were determined through liquid chromatography-tandem mass spectrometry. Plasma DNA samples were used to explore the effect of gene polymorphisms on the PK of ticagrelor and AR-C124910XX with whole-exome sequencing. Results: Female participants had a higher maximum plasma concentration/weight ratio (C max/W; p < 0.001) and a shorter half-life (T 1/2; p < 0.05) for ticagrelor than their male counterparts. In addition, a higher area under the curve/weight ratio (AUC/W; p < 0.001), and longer T 1/2 (p < 0.001) and time to reach the maximum plasma concentration (T max; p < 0.001), as well as a lower apparent drug clearance (CL/F; p < 0.001), were observed among healthy volunteers in the fed trial compared to those enrolled in the fasting trial. For AR-C124910XX, higher C max/W (p < 0.001) and AUC/W (p < 0.001) but lower CL/F (p < 0.001) and apparent volume of distribution (V d/F; p < 0.001) were observed among female participants. Healthy volunteers enrolled in the fasting trial exhibited higher C max/W (p < 0.001) and AUC/W (p < 0.01), shorter T max (p < 0.001), and lower CL/F (p < 0.001) and V d/F (p < 0.001) than those enrolled in the fed trial. Upon confirmation through multivariate analysis, the CYP4F2 rs2074900 A/A carriers were associated with higher C max/W and AUC/W and lower CL/F and V d/F than the CYP4F2 rs2074900 A/G and G/G carriers. Conclusion: This study is the first to show that the CYP4F2 rs2074900 SNP had a remarkable effect on ticagrelor PK, which is significant since it adds to the limited pharmacogenetic information on ticagrelor.
| S-EPMC8915292 | biostudies-literature
Project description:PurposeThe recent repurposing of ketamine as treatment for pain and depression has increased the need for accurate population pharmacokinetic (PK) models to inform the design of new clinical trials. Therefore, the objectives of this study were to externally validate available PK models on (S)-(nor)ketamine concentrations with in-house data and to improve the best performing model when necessary.MethodsBased on predefined criteria, five models were selected from literature. Data of two previously performed clinical trials on (S)-ketamine administration in healthy volunteers were available for validation. The predictive performances of the selected models were compared through visual predictive checks (VPCs) and calculation of the (root) mean (square) prediction errors (ME and RMSE). The available data was used to adapt the best performing model through alterations to the model structure and re-estimation of inter-individual variability (IIV).ResultsThe model developed by Fanta et al. (Eur J Clin Pharmacol 71:441-447, 2015) performed best at predicting the (S)-ketamine concentration over time, but failed to capture the (S)-norketamine Cmax correctly. Other models with similar population demographics and study designs had estimated relatively small distribution volumes of (S)-ketamine and thus overpredicted concentrations after start of infusion, most likely due to the influence of circulatory dynamics and sampling methodology. Model predictions were improved through a reduction in complexity of the (S)-(nor)ketamine model and re-estimation of IIV.ConclusionThe modified model resulted in accurate predictions of both (S)-ketamine and (S)-norketamine and thereby provides a solid foundation for future simulation studies of (S)-(nor)ketamine PK in healthy volunteers after (S)-ketamine infusion.
| S-EPMC8275530 | biostudies-literature
Project description:The investigational ticagrelor-neutralizing antibody fragment, MEDI2452, is developed to rapidly and specifically reverse the antiplatelet effects of ticagrelor. However, the dynamic interaction of ticagrelor, the ticagrelor active metabolite (TAM), and MEDI2452, makes pharmacokinetic (PK) analysis nontrivial and mathematical modeling becomes essential to unravel the complex behavior of this system. We propose a mechanistic PK model, including a special observation model for post-sampling equilibration, which is validated and refined using mouse in vivo data from four studies of combined ticagrelor-MEDI2452 treatment. Model predictions of free ticagrelor and TAM plasma concentrations are subsequently used to drive a pharmacodynamic (PD) model that successfully describes platelet aggregation data. Furthermore, the model indicates that MEDI2452-bound ticagrelor is primarily eliminated together with MEDI2452 in the kidneys, and not recycled to the plasma, thereby providing a possible scenario for the extrapolation to humans. We anticipate the modeling work to improve PK and PD understanding, experimental design, and translational confidence.
| S-EPMC5131888 | biostudies-literature
Project description:This study aimed to investigate the pharmacokinetic and pharmacodynamic (PK/PD) profiles of dotinurad, a novel uricosuric agent, and to construct a PK/PD model to predict serum urate (SUA) levels after dotinurad administration in healthy men. PK/PD model was constructed using single-dose study data considering the physiological features of urate handling. Model validation was performed by comparing the predicted SUA levels with the SUA levels in a multiple-dose study. Dotinurad was absorbed rapidly, and its exposure increased proportionally in the tested dose ranges (0.5-20 mg) after a single-dose administration. The PK model after oral administration was described using a one-compartment model with first-order absorption. Effects on SUA and renal urate excretion of dotinurad increased with dose escalation but were apparently saturable at a dose >5 mg. The simple maximal effect (E max) model was selected as the PD model of dotinurad on renal urate reabsorption, resulting in an estimated E max of 0.51. The plasma concentration at the half-maximal effect of dotinurad was 196 ng/mL. Other PD parameters were calculated from the change in SUA level or urinary excretion of urate before and after dotinurad administration. The predicted SUA levels, using the PK/PD model, were well-fitted with the observed values. The constructed PK/PD model of dotinurad appropriately described the profiles of dotinurad plasma concentrations and SUA level in multiple administration study.
| S-EPMC6880184 | biostudies-literature
Project description:BackgroundSeveral opioids are metabolized by the inducible cytochrome P450 (CYP) 3A isozymes. Coadministration with strong inducers of drug metabolism, such as rifampin, can dramatically reduce systemic exposure to these opioids. As the CYP metabolism of hydromorphone is of minor importance, we studied in healthy volunteers whether hydromorphone would be an effective analgesic for patients who concomitantly receive the prototypical enzyme inducer rifampin.MethodsIn this paired, randomized, crossover study, 12 participants received oral placebo or rifampin for 8 days. Oral hydromorphone (2.6 mg) was administered on day 6 followed by intravenous hydromorphone (0.02 mg/kg) on day 8. Hydromorphone and hydromorphone-3-glucuronide (HM3G) plasma concentrations were measured for 24 hours and psychomotor responses, including perceived drug effect, change in pupil diameter, and cold pressor threshold were evaluated for 6 hours. Our primary outcome was the change in the area under the concentration-time curve (AUC0-last) of oral and intravenous hydromorphone after pretreatment with rifampin or placebo. Pharmacodynamic parameters and other pharmacokinetic parameters were analyzed as secondary outcomes.ResultsRifampin reduced the AUC0-last of oral and intravenous hydromorphone by 43% (ratio to control: 0.57, 90% confidence interval [CI], 0.50-0.65) and 26% (ratio to control: 0.74, 90% CI, 0.69-0.79), respectively. The maximum concentration of oral hydromorphone was reduced by 37% (ratio to control: 0.63, 90% CI, 0.55-0.72), and oral bioavailability decreased from 33% to 26% (ratio to control: 0.78, 90% CI, 0.67-0.91) in the rifampin phase compared with placebo. The HM3G-to-hydromorphone ratio increased by 50% (90% CI, 25-79) and 42% (90% CI, 29-55) after oral and intravenous hydromorphone, respectively. Rifampin did not significantly affect the pharmacodynamic parameters.ConclusionsRifampin significantly reduces the concentrations of oral and intravenous hydromorphone. This interaction is due to an increase in the first-pass and systemic metabolism of hydromorphone, likely involving induction of uridine 5'-diphospho- glucuronosyltransferase enzymes by rifampin. The enhancement of hydromorphone elimination should be considered when managing pain of patients who are treated with strong enzyme inducers.
| S-EPMC8257471 | biostudies-literature
Project description:Dabigatran etexilate (DABE) is a direct oral anticoagulant (DOAC) and may be combined with ticagrelor, a P2Y12 inhibitor with antiplatelet effects. This combination of antiplatelet drugs and anticoagulants would increases the risk of bleeding in patients. In addition, the potential drug interaction may further increase the risk of bleeding. At present, there is scarce research to clarify the results of the interaction between the two. Therefore, we conducted this study to identify the potential impact of ticagrelor on the pharmacokinetics of DABE using physiologically based pharmacokinetic (PBPK) modeling. The models reasonably predicted the concentration-time profiles of dabigatran (DAB), the transformation form after DABE absorption, and ticagrelor. For pharmacokinetic drug-drug interaction (DDI), exposure to DAB at steady state was increased when co-administrated with ticagrelor. The Cmax and AUC0-t of DAB were raised by approximately 8.7% and 7.1%, respectively. Meanwhile, a stable-state ticagrelor co-administration at 400 mg once-daily increased the Cmax and AUC0-t of DAB by approximately 12.8% and 18.8%, respectively. As conclusions, Ticagrelor slightly increased the exposure of DAB. It is possible to safely use ticagrelor in a double or triple antithrombotic regimen containing DABE, only considering the antithrombotic efficacy, but not need to pay much attention on the pharmacokinetic DDI.
| S-EPMC7298054 | biostudies-literature
Project description:The objective of this population pharmacokinetic (PK) analysis was to characterize the concentration-time profile of brepocitinib plasma concentration after single- and multiple-oral administration in healthy volunteers (HVs) and patients with immuno-inflammatory diseases. Blood samples from phase I HV and phase II clinical studies of patients with alopecia areata, psoriasis, psoriatic arthritis, ulcerative colitis (UC), vitiligo, and hidradenitis suppurativa were analyzed using a nonlinear mixed-effects modeling approach. Effects of patients' characteristics on brepocitinib exposure were investigated. Overall, 8552 brepocitinib plasma concentrations from 775 individuals were included in the analysis. The PKs of brepocitinib were adequately described by a two-compartment model with first-order absorption and a lag time for tablet formulation, dose-dependent bioavailability, and Box-Cox transformed interindividual variabilities on apparent clearance (CL/F) and apparent central volume of distribution (Vc/F). For a typical 70-kg non-Asian female patient with baseline aspartate aminotransferase of 22 unit/liter, CL/F and Vc/F estimates were 17.5 L/h and 88.5 L, respectively. Asians had a higher exposure (independent of body weight), caused by a 10% lower CL/F when compared to other individuals. Independent of baseline body weight, the male population showed 13% higher Vc/F compared to the female population. Patients with UC were predicted to have 46% slower absorption rate compared to other individuals. The PKs of brepocitinib were well-characterized by a two-compartment model with first-order absorption and dose-dependent bioavailability. Several covariates, such as race and sex, were identified to have statistically significant, but not clinically meaningful, effects on the estimated PK parameters.
| S-EPMC11015086 | biostudies-literature
Project description:Intravenous (i.v.) morphine is a safe, robust, and recommended treatment for severe pain using the titration principle. Despite its high efficacy, it is impacted by organizational constraints related to venous access. Nebulized (NEB) morphine may represent an alternative for titration but pharmacokinetic (PK) properties of short nebulization using routine devices need evaluation. Twenty-seven healthy volunteers were included to receive NEB or i.v. morphine administration using increasing amounts according to Dixon's reference method. Plasma morphine, morphine-3-glucuronide (M3G), and morphine-6-glucuronide (M6G) were quantified. PK modeling and simulations were performed using Monolix. Dixon's method exhibited a significantly higher morphine dose regimen in the NEB group versus the i.v. group (6.2 [5.3-7.1] vs. 3.0 [2.0-4.0] mg, p < 0.001). Morphine, M3G, and M6G dose-normalized exposure were significantly lower in the NEB group versus the i.v. group: morphine (19 [13-23] vs. 1044 [702-1266] µg min/L, p < 0.001), M3G (245 [162-287] vs. 3752 [2487-5165] µg min/L, p < 0.001) and M6G (28 [21-43] vs. 466 [370-723] µg min/L, p < 0.001). The model that best fitted the data consisted in a transit compartment for morphine absorption, three compartments for morphine distribution followed by multiple transit compartments (8.2 and 57.5-min transit time for M3G and M6G, respectively) and a first order elimination for M3G and M6G. Morphine bioavailability in the NEB group was 3.5% using the i.v. group as reference. Administration route and sex significantly influenced morphine and metabolite PKs. This work aimed to evaluate the PKs of NEB morphine compared with the i.v. route. Despite a bioavailability to improve, NEB morphine administration using a routine device is suitable to plan morphine titration.
| S-EPMC8752103 | biostudies-literature