Meta‐Analysis of Non‐Compartmental Pharmacokinetic Parameters of Ertugliflozin to Evaluate Dose Proportionality and UGT1A9 Polymorphism Effect on Exposure

Aim: Phenytoin is metabolized through CYP2C9 and CYP2C19 . Polymorphisms of CYP2C9 and CYP2C19 may increase plasma concentration and side effects. Materials & methods: Systematic review and meta-analysis were performed to evaluate the effects of CYP2C9 and CYP2C19 polymorphism on pharmacokinetic parameters. PubMed, Science Direct, Cochrane library, and Thai databases were systematically searched. Results: Eight observational studies, comprising a total of 633 patients were included. Michaelis–Menten constant was significantly higher in the polymorphism of CYP2C9IM/CYP2C19EM and CYP2C9IM/CYP2C19IM groups as compared with the control groups (CYP2C9EM/CYP2C19EM) at 2.16 and 1.55 mg/l (p < 0.00001, p < 0.0001). The maximum rate of action was significantly lower in the control groups as compared with the polymorphism of CYP2C9IM/CYP2C19EM and CYP2C9IM/CYP2C19IM groups at 3.10 and 3.53 mg/kg/day (p = 0.00001, <0.0001). Conclusion: The dosage regimen for patients in the CYP2C9IM group to achieve phenytoin therapeutic levels was 2.1–3.4 mg/kg/day.

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DO WE HAVE A CONSENSUS TO APPLY MODEL-BASED AMINOGLYCOSIDE THERAPY: A REVIEW OF POPULATION PHARMACOKINETIC MODELS

Archives of Disease in Childhood ◽

10.1136/archdischild-2015-310148.55 ◽

2015 ◽

Vol 101 (1) ◽

pp. e1.51-e1

Author(s):

Guo-Xiang Hao ◽

Sophie Teng ◽

Evelyne Jacqz-Aigrain ◽

Wei Zhao

Keyword(s):

Meta Analysis ◽

Pharmacokinetic Modeling ◽

Pharmacokinetic Parameters ◽

Population Pharmacokinetic ◽

Pharmacokinetic Models ◽

Related Factors ◽

Model Based ◽

Aminoglycoside Therapy ◽

Bibliographic Search ◽

Adults And Children

Background and ObjectiveAminoglycosides remain the standard antibiotic therapy for Gram-negative infections in both adults and children. The pharmacokinetic modeling approach has been widely used to evaluate aminoglycosides therapy. The aim of the present study is to review the published population pharmacokinetic models of commonly used aminoglycosides (gentamycin, amikacin and tobramycin), in order to determine if there was a consensus to apply model-based personalized aminoglycoside therapy in routine clinical practice.MethodsThe bibliographic search was performed electronically using PubMed on 30th January 2015, following the search strategy: “((population Pharmacokinetics) OR (Pharmacokinetic modeling)) AND (gentamycin OR gentamicin OR amikacin OR tobramycin)”.ResultsA total of 49 articles were identified. Persistent variabilities exist in terms of structure model; typical pharmacokinetic parameters and identified covariates.ConclusionA pharmacokinetic meta-analysis is required to evaluate the study-related factors influencing the pharmacokinetics of aminoglycosides. A clinical evaluation of pharmacokinetic model of aminoglycosides is required to demonstrate its clinical utility.

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Pharmacokinetics of the New Ketolide Telithromycin (HMR 3647) Administered in Ascending Single and Multiple Doses

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.45.1.170-175.2001 ◽

2001 ◽

Vol 45 (1) ◽

pp. 170-175 ◽

Cited By ~ 89

Author(s):

F. Namour ◽

D. H. Wessels ◽

M. H. Pascual ◽

D. Reynolds ◽

E. Sultan ◽

...

Keyword(s):

Oral Dose ◽

Plasma Concentrations ◽

Dose Proportionality ◽

Pharmacokinetic Parameters ◽

Respiratory Pathogens ◽

Multiple Dosing ◽

Time Curve ◽

Once Daily ◽

Days Of Therapy ◽

Tract Infections

ABSTRACT Telithromycin (HMR 3647) is a novel ketolide antimicrobial with good activity against both common and atypical respiratory pathogens, including many resistant strains. This randomized, three-period crossover study determined the dose proportionality of telithromycin pharmacokinetics after single and multiple dosing in healthy subjects. In each treatment period, subjects received a single oral dose of 400, 800 or 1,600 mg of telithromycin followed 4 days later by the same dose once daily for 7 days. Blood and urine samples were taken throughout the study for determination of pharmacokinetic parameters for telithromycin and RU 76363, its main metabolite. Telithromycin and RU 76363 achieved steady state within 2 to 3 days of once-daily dosing. A slight accumulation of telithromycin was observed after 7 days of therapy, with values of the area under the concentration-time curve from 0 to 24 h approximately 1.5 times higher than those achieved with the single dose. The pharmacokinetics of telithromycin and RU 76363 deviated moderately from dose proportionality. At a dose of 800 mg/day, telithromycin attained mean maximal and trough plasma concentrations of 2.27 and 0.070 mg/liter respectively. Elimination was biphasic; initial and terminal half-lives were 2.87 and 9.81 h for the 800-mg dose. Study medication was well tolerated, although adverse events tended to be more frequent at the 1,600-mg dose. This study showed that telithromycin was generally well tolerated and suggests that a once-daily 800-mg oral dose of telithromycin maintains an effective concentration in plasma for the treatment of respiratory tract infections involving the key respiratory pathogens.

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PK-DB: PharmacoKinetics DataBase for Individualized and Stratified Computational Modeling

10.1101/760884 ◽

2019 ◽

Author(s):

Jan Grzegorzewski ◽

Janosch Brandhorst ◽

Dimitra Eleftheriadou ◽

Kathleen Green ◽

Matthias König

Keyword(s):

Computational Modeling ◽

Computational Models ◽

Smoking Status ◽

Meta Analysis ◽

Area Under The Curve ◽

Pharmacokinetic Parameters ◽

Population Pharmacokinetic ◽

Special Focus ◽

Biological Ontologies ◽

Time Courses

ABSTRACTA multitude of pharmacokinetics studies have been published. However, due to the lack of an open database, pharmacokinetics data, as well as the corresponding meta-information, have been difficult to access. We present PK-DB (https://pk-db.com), an open database for pharmacokinetics information from clinical trials including pre-clinical research. PK-DB provides curated information on (i) characteristics of studied patient cohorts and subjects (e.g. age, bodyweight, smoking status); (ii) applied interventions (e.g. dosing, substance, route of application); (iii) measured pharmacokinetic time-courses; (iv) pharmacokinetic parameters (e.g. clearance, half-life, area under the curve). Key features are the representation of experimental errors, the normalization of measurement units, annotation of information to biological ontologies, calculation of pharmacokinetic parameters from concentration-time profiles, a workflow for collaborative data curation, strong validation rules on the data, computational access via a REST API as well as human access via a web interface. PK-DB enables meta-analysis based on data from multiple studies and data integration with computational models. A special focus lies on meta-data relevant for individualized and stratified computational modeling with methods like physiologically based pharmacokinetic (PBPK), pharmacokinetic/pharmacodynamic (PK/DB), or population pharmacokinetic (pop PK) modeling.

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A Network Meta-Analysis of the Efficacy and Safety of Empagliflozin at Different Doses in Patients with Diabetes Mellitus Based on Randomized Controlled Trials

10.21203/rs.3.rs-32579/v1 ◽

2020 ◽

Author(s):

Qian Wu ◽

Chen Liao ◽

Mengyu He ◽

Can Li ◽

Fang Zou ◽

...

Keyword(s):

Randomized Controlled Trials ◽

Dose Response ◽

Meta Analysis ◽

Cochrane Library ◽

Pharmacokinetic Parameters ◽

Controlled Trials ◽

Low Doses ◽

Randomized Controlled ◽

High Doses ◽

Different Doses

Abstract Background and objective: As an oral hypoglycemic drug that significantly reduces cardiovascular risk, empagliflozin is used in patients with type 2 diabetes. However, the dosage and administration of empagliflozin are still controversial clinically. To determine the appropriate treatment, we performed this network meta-analysis.Methods: We identified randomized controlled trials (RCTs) about empagliflozin from databases including PubMed, Ovid MEDLINE, Embase, ScienceDirect, Web of Science, the Cochrane Library, Scopus and Google Scholar. We analyzed the pharmacodynamics, adverse effects (AEs), and pharmacokinetics of empagliflozin at different doses.Results: We identified 8264 articles, of which 26 RCTs with 11796 patients were included. Regarding hemoglobin A1c (HbA1c ) and fasting plasma glucose (FPG), high doses (10, 25, 50 mg) were significantly better than low doses (1, 2.5, 5 mg). For total AEs, there was a dose-response trend in which safety decreased with increasing doses. According to SUCRA sequencing, the order for lowering HbA1c was 25 > 50 > 10 > 2.5 > 5 > 1 mg, for lowering FPG was 50 > 25 > 10 > 5 > 2.5 > 1 mg and for safety was 1 > 2.5 > 5 > 25 > 10 > 50 mg. When considering HbA1c, FPG and total AEs, we performed a hierarchical cluster analysis and network meta-analysis to find that 25 mg performed best among different doses, which was more significant after long-term use (≥ 12 weeks). Pharmacokinetic parameters exhibited significant dose-response relationships .Conclusions: High doses (10, 25, 50 mg) had better efficacy than low doses (1, 2.5, 5 mg). When considering HbA1c, FPG and total AEs, 25 mg performed best among the different doses. More RCTs exploring unconventional doses are needed to confirm these conclusions.

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The Associations Between CYP2D6*10 C188T Polymorphism and Pharmacokinetics and Clinical Outcomes of Tramadol: A Systematic Review and Meta-analysis

Pain Medicine ◽

10.1093/pm/pnaa140 ◽

2020 ◽

Vol 21 (12) ◽

pp. 3679-3690 ◽

Cited By ~ 2

Author(s):

Qing-Hua Wen ◽

Zheng Zhang ◽

Wen-Ke Cai ◽

Xiao-Qian Lin ◽

Gong-Hao He

Keyword(s):

Clinical Outcomes ◽

Meta Analysis ◽

Postoperative Nausea And Vomiting ◽

Opioid Analgesics ◽

Visual Analog Scale Score ◽

Nausea And Vomiting ◽

Cochrane Library ◽

Pharmacokinetic Parameters ◽

Total Consumption ◽

The Cochrane Library

Abstract Background Tramadol is one of the most extensively used centrally acting synthetic opioid analgesics. Recently, a number of studies have explored the associations of the CYP2D6*10 C188T polymorphism with pharmacokinetic and clinical outcomes of tramadol. However, the results of these previous reports remain controversial. Therefore, a meta-analysis was needed to reach a consensus. Methods PubMed, EMBASE, and the Cochrane Library were searched to identify eligible studies that explored the influence of the CYP2D6*10 C188T polymorphism on clinical outcomes of tramadol through April 2019. Articles meeting the inclusion criteria were comprehensively reviewed by two independent evaluators. A meta-analysis was performed using Review Manager 5.3. Results A total of nine studies involving 809 related subjects were included in this meta-analysis. Significant associations were found between CYP2D6*10 C188T mutation and longer serum tramadol half-lives, larger AUC0-∞, and the slower clearance rate of tramadol. In addition, we also found that CYP2D6*10 C188T had effects on the pharmacokinetic parameters of the metabolite of tramadol, O-desmethyltramadol, by sensitive analysis. Furthermore, CYP2D6*10 C188T polymorphism was associated with higher visual analog scale score, loading dose, and total consumption of tramadol. There was no significant association between CYP2D6*10 C188T polymorphism and postoperative nausea and vomiting. Conclusions CYP2D6*10 C188T polymorphism had a significant influence on tramadol pharmacokinetics and analgesic effect, but there was insufficient evidence to demonstrate that this polymorphism was associated with incidence of nausea and vomiting.

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PHARMACOKINETICS OF BENZNIDAZOLE IN CHAGAS DISEASE: A SYSTEMATIC REVIEW AND META-ANALYSIS

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01567-16 ◽

2016 ◽

pp. AAC.01567-16 ◽

Cited By ~ 1

Author(s):

Matthew O. Wiens ◽

Steve Kanters ◽

Edward Mills ◽

Alejandro A. Peregrina Lucano ◽

Silvia Gold ◽

...

Keyword(s):

Chagas Disease ◽

Meta Analysis ◽

Volume Of Distribution ◽

Systematic Search ◽

Pharmacokinetic Parameters ◽

Oral Clearance ◽

100Mg Dose ◽

Patient Level ◽

Elimination Half ◽

Pharmacokinetic Properties

Background: Chagas disease is a neglected parasitic illness affecting approximately 8 million people, predominantly in Latin America. Benznidazole is the drug of choice for treatment, although availability has been limited. A paucity of knowledge of the pharmacokinetic properties of this drug have contributed to limited availability in several jurisdictions.Objective: To conduct systematic literature review and Bayesian meta-analysis of pharmacokinetic studies to improve estimates of basic pharmacokinetic properties of benznidazole.Methods: A systematic search of Embase, Medline, LILACS and Scielo was conducted. Eligible studies reported patient-level data from single 100mg dose pharmacokinetic evaluations of benznidazole in adults, or otherwise provided data relevant to the estimation of pharmacokinetic parameters which could be derived from such studies. A Bayesian hierarchical model was used for analysis. The use of secondary data (i.e. studies that did not include patient level, single 100mg dose data) was used for the generation of empiric priors for the Bayesian analysis.Results: The systematic search identified nine studies for inclusion. Nine pharmacokinetic parameters were estimated including AUC, Cmax, Tmax, elimination (Kelim) and absorption (Ka) rate constants, absorption and elimination half-life, apparent oral clearance and apparent oral volume of distribution. The results showed consistency across studies. The AUC and Cmax were 51.31mg*h/L (95% CrI: 45.01, 60.28) and 2.19mg/L (95% CrI: 2.06, 2.33), respectively. The ka and Kelim were 1.16h-1(95% CrI; 0.59, 1.76) and 0.052h-1(95% CrI; 0.045, 0.059), respectively, with corresponding absorption and elimination half-lives of 0.60h (95% CrI; 0.38, 1.11) and 13.27h (95% CrI; 11.79, 15.42). The oral clearance and volume of distribution were 2.04L/h (95%CrI 1.77, 2.32) and 39.19L (95%CrI; 36.58, 42.17), respectively.Conclusions: A Bayesian meta-analysis was used to improve estimates of the standard pharmacokinetic parameters of benznidazole. This data can inform clinicians and policymakers as access to this drug increases.

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Simultaneous Quantification of Pioglitazone and Omarigliptin in Rat Plasma by UHPLC-MS/MS and Its Application to Pharmacokinetic Study after Coadministration of the Two Drugs

Journal of Analytical Methods in Chemistry ◽

10.1155/2021/6693366 ◽

2021 ◽

Vol 2021 ◽

pp. 1-9

Author(s):

Lin Wang ◽

Jiaxi Wang ◽

Chao Lin ◽

Furong Wang ◽

Xiangping Li ◽

...

Keyword(s):

Pharmacokinetic Study ◽

Meta Analysis ◽

Internal Standard ◽

Gradient Elution ◽

Rat Plasma ◽

Ion Source ◽

Pharmacokinetic Parameters ◽

Column Temperature ◽

Linear Relationships ◽

Long Acting

Combination therapy is a common approach for clinical treatment of type 2 diabetes mellitus, especially for patients with poor monotherapy. Meta-analysis suggested that omarigliptin, a long-acting DPP-4 inhibitor, combined with pioglitazone might improve the side effects of pioglitazone. However, little is known about the pharmacokinetic properties after a coadministration. In this study, a rapid and reliable method for the simultaneous determination of the pioglitazone and omarigliptin in rat plasma by UHPLC-MS/MS was established and validated for the first time. An exsil mono C18 column (2.0 × 50 mm, 3 μm) was used to separate the analytes and the column temperature was kept at 30°C. Sitagliptin was selected as the internal standard. 0.02% formic acid aqueous solution (A) and methanol-acetonitrile (B) were used as mobile phases with gradient elution at a flow rate of 0.3 mL/min. The elution procedure was as follows: 20%B (0–0.1 min), 80%B (0.1–0.3 min), 80%B (0.3–2.0 min), and 20%B (2.1–3.0 min). A multiple reaction monitor (MRM) was used under positive ionization mode with electrospray ion source to detect pioglitazone (357.1 ⟶ 134.1), omarigliptin (399.2 ⟶ 153.0), and sitagliptin (408.2 ⟶ 235.0). The linear ranges of pioglitazone and omarigliptin were 5–2000 ng/mL and 10–4000 ng/mL, respectively. Good linear relationships were exhibited in the corresponding linear ranges (r ≥ 0.9944). The bioanalytical method was validated, and the selectivity, linearity, sensitivity, accuracy, precision, stability, recovery, and matrix effect were acceptable. The validated method was then successfully applied to pharmacokinetic study of pioglitazone combined with omarigliptin in rats. Results suggested that the combination of the two drugs had little effect on the pharmacokinetic parameters of each other in rats.

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Meta-analysis of the effect of CYP2B6, CYP2A6, UGT2B7 and CAR polymorphisms on efavirenz plasma concentrations

Journal of Antimicrobial Chemotherapy ◽

10.1093/jac/dkz329 ◽

2019 ◽

Vol 74 (11) ◽

pp. 3281-3290 ◽

Cited By ~ 6

Author(s):

Pedro Ayuso ◽

Megan Neary ◽

Justin Chiong ◽

Andrew Owen

Keyword(s):

Ethnic Differences ◽

Effect Size ◽

Meta Analysis ◽

Constitutive Androstane Receptor ◽

Plasma Concentrations ◽

Pharmacokinetic Parameters ◽

Primary Metabolism ◽

Standard Mean Difference ◽

The Impact ◽

Review Manager

Abstract Background Efavirenz primary metabolism is catalysed by CYP2B6 with minor involvement of CYP2A6. Subsequently, phase I metabolites are conjugated by UGT2B7, and constitutive androstane receptor (CAR) has been shown to transcriptionally regulate many relevant enzymes and transporters. Several polymorphisms occurring in the genes coding for these proteins have been shown to impact efavirenz pharmacokinetics in some but not all studies. Objectives A meta-analysis was performed to assess the overall effect of CYP2B6 rs3745274, CYP2A6 (rs28399454, rs8192726 and rs28399433), UGT2B7 (rs28365062 and rs7439366) and NR1I3 (rs2307424 and rs3003596) polymorphisms on mid-dose efavirenz plasma concentrations. Methods Following a literature review, pharmacokinetic parameters were compiled and a meta-analysis for these variants was performed using Review Manager and OpenMetaAnalyst. A total of 28 studies were included. Results Unsurprisingly, the analysis confirmed that individuals homozygous for the T allele for CYP2B6 rs3745274 had significantly higher efavirenz concentrations than those homozygous for the G allele [weighted standard mean difference (WSMD) = 2.98; 95% CI 2.19–3.76; P < 0.00001]. A subgroup analysis confirmed ethnic differences in frequency but with a similar effect size in each ethnic group (P = 0.96). Associations with CYP2A6 and UGT2B7 variants were not statistically significant, but T homozygosity for CAR rs2307424 was associated with significantly lower efavirenz concentrations than in C homozygotes (WSMD = −0.32; 95% CI −0.59 to −0.06; P = 0.02). Conclusions This meta-analysis provides the overall effect size for the impact of CYP2B6 rs3745274 and NR1I3 rs2307424 on efavirenz pharmacokinetics. The analysis also indicates that some previous associations were not significant when interrogated across studies.

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