Interindividual Pharmacokinetic Variability Research Articles

Microdialysis of Drug and Drug Metabolite: a Comprehensive In Vitro Analysis for Voriconazole and Voriconazole N-oxide

PurposeVoriconazole is a therapeutically challenging antifungal drug associated with high interindividual pharmacokinetic variability. As a prerequisite to performing clinical trials using the minimally-invasive sampling technique microdialysis, a comprehensive in vitro microdialysis characterization of voriconazole (VRC) and its potentially toxic N-oxide metabolite (NO) was performed.MethodsThe feasibility of simultaneous microdialysis of VRC and NO was explored in vitro by investigating the relative recovery (RR) of both compounds in the absence and presence of the other. The dependency of RR on compound combination, concentration, microdialysis catheter and study day was evaluated and quantified by linear mixed-effects modeling.ResultsMedian RR of VRC and NO during individual microdialysis were high (87.6% and 91.1%). During simultaneous microdialysis of VRC and NO, median RR did not change (87.9% and 91.1%). The linear mixed-effects model confirmed the absence of significant differences between RR of VRC and NO during individual and simultaneous microdialysis as well as between the two compounds (p > 0.05). No concentration dependency of RR was found (p = 0.284). The study day was the main source of variability (46.3%) while the microdialysis catheter only had a minor effect (4.33%). VRC retrodialysis proved feasible as catheter calibration for both compounds.ConclusionThese in vitro microdialysis results encourage the application of microdialysis in clinical trials to assess target-site concentrations of VRC and NO. This can support the generation of a coherent understanding of VRC pharmacokinetics and its sources of variability. Ultimately, a better understanding of human VRC pharmacokinetics might contribute to the development of personalized dosing strategies.

Effects of CYP3A4/5 and ABC transporter polymorphisms on osimertinib plasma concentrations in Japanese patients with non-small cell lung cancer.

The effects of polymorphisms in CYP3A4 (20230G > A), CYP3A5 (6986A > G), ABCB1 (1236C > T, 2677G > T/A, 3435C > T), ABCG2 (421C > A), and ABCC2 (-24C > T) on the area under the concentration-time curve (AUC) of osimertinib in 23 patients with non-small cell lung cancer were investigated. Blood sampling was performed just prior to and at 1, 2, 4, 6, 8, 12, and 24h after osimertinib administration at the steady-state on day 15 after beginning therapy. The osimertinib AUC0-24 was significantly correlated with age (P = 0.038), serum albumin (P = 0.002), and serum creatinine (P = 0.012). Additionally, there were significant differences in the AUC0-24 of osimertinib among the groups administered vonoprazan, histamine 2-receptor antagonists or esomeprazole, and no acid suppressants (P = 0.021). By contrast, there were no significant differences in the AUC0-24 of osimertinib between genotypes of CYP3A4/5 or ABC transporters. Furthermore, there were no significant differences in the AUC0-24 of osimertinib between patients with diarrhea, skin rash, or hepatotoxicity and those without these conditions. In multivariate analysis, only serum albumin value was an independent factor predicting the AUC0-24 of osimertinib. Analysis of CYP3A4/5 and ABC transporter polymorphisms before osimertinib therapy may not predict the efficacy or side effects of osimertinib. The lower serum albumin values were associated with an increase in the AUC0-24 of osimertinib; however, further studies are needed to assess the factors contributing to the interindividual variability of osimertinib pharmacokinetics.

242.7: Influence of CYP3A5 Polymorphisms on Tacrolimus Dosing in Renal Transplant Recipients

Introduction: Tacrolimus is a commonly used immunosuppressant after kidney transplantation it has narrow theraupetic range and demonstrates wide interindividual variability in pharmacokinetics leading to potential under immunosuppression or tacrolimus toxicity genetic polymorphism in CYP3A5 enzyme expression contributes to differences in tacrolimus bioavailibility between individuals. Aim of the study: Ti evaluate pharmacogenomic effect of CYP3A5 gene polymorphisms on tacrolimus dosing in renal transplant recipients. Materials and Methods: Present study we investigated pharmacogenomics associations of common CYP3A5 polymorphisms with requirements of tacrolimus in renal transplant patients: □INCLUSION CRITERIA - 50 patients on tacrolimus based triple immunosuppression were genotyped for cyp3A5 polymorphism most allels- *1/*1,*1/*3,*3/*3 alleles. □EXCLUSION CRITERIA- those patients on CYP inducers or inhibitors were excluded demographic data, weight based tacrolimus doses, serum tacrolimus level at 1 month, 3 months 1 year and present tacrolimus trough level were collected. Data was statistically analysed. Results: Mean age of the recipients was 33.41+/-10.2,72% were males mean tacrolimus level at 1 month was 8ng/ml (7-10ng/ml) at 1 month post transplant cyp *1/*1 was 5.75+_0.95,tac level in cyp3a5 *1/*3 was 9.52∔_1.42,CYP3A5*3/*3 -10.26+_1.02 with significant P VALUE <0.01 among patients with high tac level 36% were poor metabolisers,50% intermediate metabolizers,none of the extensive metabolisers had higher tacrolimus level. At>3 months of transplantation tac level in cyp3a5 *1/*1 was 5.75∔0.95, cyp3a5 *1/*3 was 6.33∓1.17, cyp3a5 *3/*3 was 6.78∔-0.8 with significant P value < 0.01. 56% developed tac toxicity - 84%(*3/*3) poor metabolisers, 14.3% in intermediate *1/*3 metabolisers.125 developed rejections in first three months of transplant,90.755 were extensive metabolisers Discussion: Tacrolimus toxicity as well as rejection due to sub theraupetic levels influence graft outcomes. bioavailibility of tacrolimus varies widely due to gene polymorphisms of CYP3A5 gene. CYP3A5*1/*1 had lower tac level in blood resulting higher rates of rejection requiring 1.5 to 2 times higher dose compared to poor metabolisersand intermediate metabolizers. Poor metabolizers *3/*3 had tacrolimus related toxicity at similar dose adjusted tac levels, indicating lower dose for maintanence (0.06mg/kg). Conclusion: Genotyped based dosing may improve achievement of theraupetic drug concentrations with reduced drug related complications in the era of personalised medicine.

Genomewide association study identifies a novel variant associated with tacrolimus trough concentration in Chinese renal transplant recipients.

Tacrolimus (TAC) is an immunosuppressant widely used in kidney transplantation. TAC displays considerable interindividual variability in pharmacokinetics (PKs). Genetic and clinical factors play important roles in TAC PKs. We enrolled a total of 251 Chinese renal transplant recipients and conducted a genomewide association study (GWAS), linkage disequilibrium (LD), and one-way analysis of variance (ANOVA) to find genetic variants affecting log-transformed TAC trough blood concentration/dose ratio (log[C0 /D]). In addition, we performed dual luciferase reporter gene assays and multivariate regression models to evaluate the effect of the genetic variants. The GWAS results showed that all 23 genomewide significant single-nucleotide polymorphisms (p < 5 × 10-8 ) were located on chromosome 7, including CYP3A5*3. LD, conditional association analysis, and one-way ANOVA showed that rs75125371 T > C independently influenced TAC log(C0 /D). Dual luciferase reporter gene assays indicated that rs75125371 minor allele (C) was significantly associated with increased normalized luciferase activity than the major allele (T) in the Huh7 cells (p=1.2 × 10-5 ) and HepaRG cells (p=0.0097). A model inclusive of age, sex, hematocrit, CYP3A5*3, and rs75125371 explained 37.34% variance in TAC C0 . These results suggest that rs75125371 T > C is a functional and population-specific variant affecting TAC C0 in Chinese renal transplant recipients.

Therapeutic Drug Monitoring of Ivacaftor, Lumacaftor, Tezacaftor, and Elexacaftor in Cystic Fibrosis: Where Are We Now?

Drugs modulating the cystic fibrosis transmembrane conductance regulator (CFTR) protein, namely ivacaftor, lumacaftor, tezacaftor, and elexacaftor, are currently revolutionizing the management of patients with cystic fibrosis (CF), particularly those with at least one F508del variant (up to 85% of patients). These “caftor” drugs are mainly metabolized by cytochromes P450 3A, whose enzymatic activity is influenced by environmental factors, and are sensitive to inhibition and induction. Hence, CFTR modulators are characterized by an important interindividual pharmacokinetic variability and are also prone to drug–drug interactions. However, these CFTR modulators are given at standardized dosages, while they meet all criteria for a formal therapeutic drug monitoring (TDM) program that should be considered in cases of clinical toxicity, less-than-expected clinical response, drug or food interactions, distinct patient subgroups (i.e., pediatrics), and for monitoring short-term adherence. While the information on CFTR drug exposure–clinical response relationships is still limited, we review the current evidence of the potential interest in the TDM of caftor drugs in real-life settings.

Interpatient variability in the pharmacokinetics of remdesivir and its main metabolite GS-441524 in treated COVID-19 subjects.

BackgroundRemdesivir is the first antiviral drug against SARS-CoV-2 approved for use in COVID-19 patients.ObjectivesTo study the pharmacokinetic inter-individual variability of remdesivir and its main metabolite GS-441524 in a real-world setting of COVID-19 inpatients and to identify possible associations with different demographic/biochemical variables.MethodsInpatients affected by SARS-CoV-2 infections, undergoing standard-dose remdesivir treatment, were prospectively enrolled. Blood samples were collected on day 4, immediately after (C0) and at 1 h (C1) and 24 h (C24) after infusion. Remdesivir and GS-441524 concentrations were measured using a validated UHPLC-MS/MS method and the AUC0–24 was calculated. At baseline, COVID-19 severity (ICU or no ICU), sex, age, BMI and renal and liver functions were assessed. Transaminases and estimated glomerular filtration rate (e-GFR) were also evaluated during treatment. Linear regression, logistic regression and multiple linear regression tests were used for statistical comparisons of pharmacokinetic parameters and variables.ResultsEighty-five patients were included. The mean (CV%) values of remdesivir were: C0 2091 (99.1%) ng/mL, C1 139.7 (272.4%) ng/mL and AUC0–24 2791 (175.7%) ng·h/mL. The mean (CV%) values of GS-441524 were: C0 90.2 (49.5%) ng/mL, C1 104.9 (46.6%) ng/mL, C24 58.4 (66.9) ng/mL and AUC0–24 1976 (52.6%) ng·h/mL. The multiple regression analysis showed that age (P < 0.05) and e-GFR (P < 0.01) were independent predictors of GS-441524 plasma exposure.ConclusionsOur results showed a high interpatient variability of remdesivir and GS-441524 likely due to both age and renal function in COVID-19 inpatients. Further research is required to understand whether the pharmacokinetics of remdesivir and its metabolites may influence drug-related efficacy or toxic effect.

Dose Individualization of Oral Multi-Kinase Inhibitors for the Implementation of Therapeutic Drug Monitoring.

Oral multi-kinase inhibitors have transformed the treatment landscape for various cancer types and provided significant improvements in clinical outcomes. These agents are mainly approved at fixed doses, but the large inter-individual variability in pharmacokinetics and pharmacodynamics (efficacy and safety) has been an unsolved clinical issue. For example, certain patients treated with oral multi-kinase inhibitors at standard doses have severe adverse effects and require dose reduction and discontinuation, yet other patients have a suboptimal response to these drugs. Consequently, optimizing the dosing of oral multi-kinase inhibitors is important to prevent over-dosing or under-dosing. To date, multiple studies on the exposure-efficacy/toxicity relationship of molecular targeted therapy have been attempted for the implementation of therapeutic drug monitoring (TDM) strategies. In this milieu, we recently conducted research on several multi-kinase inhibitors, such as sunitinib, pazopanib, sorafenib, and lenvatinib, with the aim to optimize their treatment efficacy using a pharmacokinetic/pharmacodynamic approach. Among them, sunitinib use is an example of successful TDM implementation. Sunitinib demonstrated a significant correlation between drug exposure and treatment efficacy or toxicities. As a result, TDM services for sunitinib has been covered by the National Health Insurance program in Japan since April 2018. Additionally, other multi-kinase targeted anticancer drugs have promising data regarding the exposure-efficacy/toxicity relationship, suggesting the possibility of personalization of drug dosage. In this review, we provide a comprehensive summary of the clinical evidence for dose individualization of multi-kinase inhibitors and discuss the utility of TDM of multi-kinase inhibitors, especially sunitinib, pazopanib, sorafenib, and lenvatinib.

The Pharmacokinetics and Pharmacogenomics of Psychostimulants.

The psychostimulants-amphetamine and methylphenidate-have been in clinical use for well more than 60 years. In general, both stimulants are rapidly absorbed with relatively poor bioavailability and short half-lives. The pharmacokinetics of both stimulants are generally linear and dose proportional although substantial interindividual variability in pharmacokinetics is in evidence. Amphetamine (AMP) is highly metabolized by several oxidative enzymes forming multiple metabolites while methylphenidate (MPH) is primarily metabolized by hydrolysis to the inactive metabolite ritalinic acid. At present, pharmacogenomic testing as an aid to guide dosing and personalized treatment cannot be recommended for either agent. Few pharmacokinetically based drug-drug interactions (DDIs) have been documented for either stimulant.

Development of UHPLC-MS/MS methods to quantify 25 antihypertensive drugs in serum in a cohort of patients treated for hypertension

We developed three ultra-high pressure liquid chromatography coupled to mass spectrometry detection (UHPLC-MS/MS) methods to quantify 25 antihypertensive drugs in serum samples. Patient-reported drug lists were collected, and drug concentrations were analysed in samples from 547 patients, half with uncontrolled hypertension, and all treated with ≥ 2 antihypertensive drugs.For sample preparation, serum was mixed with deuterated internal standards and acetonitrile and precipitated. Aliquots of the supernatant were injected on UHPLC-MSMS with a C18 reversed phase column. The mobile phase was 0.1 % HCOOH (formic acid) in water and 0.1 % HCOOH in acetonitrile (except in methanol for spironolactone/canrenone) at a flow rate of 0.4 mL/min. The calibrators and internal controls were prepared in Autonorm™. The calibration ranges were wide, and the models were linear or quadratic with squared correlation coefficients ≥ 0.97. The limits of detection and quantification, specificity, carry-over, and matrix effects were acceptable. The accuracy of the internal controls was in the range 85–121 %, and the intermediate precision for all drugs was 4–28 %.The patient-reported antihypertensive drug use and the detected serum drug concentrations were in accordance with that most frequently prescribed nationally. The percent non-detectable level was 5–10 % for bendroflumethiazide, doxazosin, nifedipine, and ramipril. Often the drug dose chosen was lower than the recommended maximum daily dose. We report the maximum (Cmax) and minimum (Cmin) drug concentrations after drug intake. The inter-individual pharmacokinetic variability at Cmin was 18-fold for hydrochlorothiazide, 22-fold for losartan carboxyl acid, 26-fold for amlodipine, 44-fold for candesartan, and 50-fold for valsartan.Our methods are suitable for measuring antihypertensive drugs in patient serum for therapy control.

Quantitation of mycophenolic acid and metabolites by UPLC-MS/MS in renal transplant patients

Mycophenolate mofetil (MMF) and enteric-coated mycophenolate sodium (EC-MPS), specific inhibitors of lymphocyte proliferation, are commonly used as adjuvant therapy with calcineurin inhibitor agents after kidney transplantation. After administration, MMF and EC-MPS are hydrolyzed to mycophenolic acid (MPA), the active form of the drug, which must be monitored due to its narrow therapeutic window, drug–drug interactions, and large intra-and inter-individual pharmacokinetic variability despite a fixed dose. Monitoring plasma MPA level is recommended to maintain the drug within the therapeutic window, optimize its efficacy, and minimize side effects. This study aims to develop a method for quantifying MPA and its major metabolites (mycophenolic acid glucuronide [MPAG]) using on-line solid phase extraction (SPE) coupled with an ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) in kidney transplant patients. The linearity of MPA and MPAG were 0.3–13.6 μg/mL and 2.6–232.9 μg/mL, respectively (r2 > 0.999). The relative error of accuracy was < 15%. The within-run and between-run imprecision was < 5.8%. No carryover, ion suppression, or ion enhancement were observed. This method was used to analysis of 351 plasma samples from renal transplant patients after MMF or EC-MPS using this method showed large pharmacokinetic variability between patients. Analysis of the same samples by

Effect of Genetic Variations in Drug-Metabolizing Enzymes and Drug Transporters on the Pharmacokinetics of Rifamycins: A Systematic Review.

BackgroundRifamycins are a novel class of antibiotics clinically approved for tuberculosis chemotherapy. They are characterized by high inter-individual variation in pharmacokinetics. This systematic review aims to present the contribution of genetic variations in drug-metabolizing enzymes and transporter proteins to the inter-individual variation of rifamycin pharmacokinetics.MethodWe followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement guidelines. The search for relevant studies was done through PubMed, Embase, Web of Science, and Scopus databases. Studies reporting single nucleotide polymorphism in drug transporters and metabolizing enzymes’ influence on rifamycin pharmacokinetics were solely included. Two reviewers independently performed data extraction.ResultsThe search identified 117 articles of which 15 fulfilled the eligibility criteria and were included in the final data synthesis. The single nucleotides polymorphism in the drug transporters SLCO1B1 rs4149032, rs2306283, rs11045819, and ABCB1 rs1045642 for rifampicin, drug metabolizing enzyme AADAC rs1803155 for rifapentine and CES2 c.-22263A>G (g.738A>G) for rifampicin partly contributes to the variability of pharmacokinetic parameters in tuberculosis patients.ConclusionThe pharmacokinetics of rifamycins is influenced by genetic variation of drug-metabolizing enzymes and transporters. Controlled clinical studies are, however, required to establish these relationships.

Docetaxel population pharmacokinetic modelling and simulation in Chinese cancer patients.

BackgroundDocetaxel is a widely prescribed cytotoxic chemotherapy drug for various cancers and the main dose-limiting toxicity is dose-dependent neutropenia. In China, the current dose regimen for docetaxel frequently results in high inter-individual pharmacokinetic (PK) variability. There is a very urgent need to establish a population PK model of docetaxel for Chinese cancer patients, to predict the area under the curve (AUC) based on the PK model and avoid toxicity, providing optimal drug dose guidance to clinicians.MethodsDocetaxel was administered at a dose of 75 mg/m2 once every 3 weeks, and at the scheduled time, blood samples were collected to measure the docetaxel concentration. A nonlinear, mixed-effects modelling approach was used to fit the plasma concentration-time data. A two-compartmental model was selected to characterize the in vivo behavior of docetaxel. Using population modelling, various covariates were explored to ascertain their impact on the docetaxel PK. Monte Carlo simulations were performed to derive the optimal individualized dose regimen.ResultsA total of 440 patients with 880 concentration data were collected. The covariate selection indicated that age, body mass index (BMI), and body surface area (BSA) had significant correlations with docetaxel clearance (CL). Bootstrap and visual predictive check (VPC) indicated that a robust and reliable PK model had been established. The final population model was effectively used for simulation to determine docetaxel dose regimens for Chinese cancer patients. Aiming an AUC <2.6 mg/L·h, a simple to use dose regimen was derived based on Monte Carlo simulations.ConclusionsA population PK model of docetaxel for Chinese cancer patients was developed and validated, showing that age, BMI, and BSA were significantly associated with CL. A simple to use dose regimen table was created to guide clinicians.

Key Factors in Effective Patient-Tailored Dosing of Fluoroquinolones in Urological Infections: Interindividual Pharmacokinetic and Pharmacodynamic Variability.

Fluoroquinolones (FQs) are a critical group of antimicrobials prescribed in urological infections as they have a broad antimicrobial spectrum of activity and a favorable tissue penetration at the site of infection. However, their clinical practice is not problem-free of treatment failure, risk of emergence of resistance, and rare but important adverse effects. Due to their critical role in clinical improvement, understanding the dose-response relation is necessary to optimize the effectiveness of FQs therapy, as it is essential to select the right antibiotic at the right dose for the right duration in urological infections. The aim of this study was to review the published literature about inter-individual variability in pharmacological processes that can be responsible for the clinical response after empiric dose for the most commonly prescribed urological FQs: ciprofloxacin, levofloxacin, and moxifloxacin. Interindividual pharmacokinetic (PK) variability, particularly in elimination, may contribute to treatment failure. Clearance related to creatinine clearance should be specifically considered for ciprofloxacin and levofloxacin. Likewise, today, undesired interregional variability in FQs antimicrobial activity against certain microorganisms exists. FQs pharmacology, patient-specific characteristics, and the identity of the local infecting organism are key factors in determining clinical outcomes in FQs use.

Ceftazidime dosing in obese patients: is it time for more?

Introduction Ceftazidime is used for the treatment of many bacterial infections, including severe P. aeruginosa infections. Like other beta-lactams, inter-individual variability in ceftazidime pharmacokinetics has been described. Due to its related pathophysiological modifications, obesity might influence ceftazidime pharmacokinetics. Areas covered The objective of this review is to assess the current state of knowledge about the impact of obesity on ceftazidime treatment. A literature search was conducted on PubMed-MEDLINE (2016-2021) to retrieve pharmacokinetic studies published in English matching the terms “ceftazidime” AND “pharmacokinetics”. Expert opinion The impact of obesity on pharmacokinetics is generally poorly known, mainly because obese patients are often excluded from clinical studies. However, the published literature clearly shows that obese patients have significantly lower ceftazidime concentrations. This could be explained by increased volume of distribution and clearance. This low exposure represents a major factor of therapeutic failure, potentially fatal for critically-ill patients. While further studies would be useful to better assess the magnitude and understanding of this variability, the use of higher doses of ceftazidime is needed in obese patients. Moreover, therapeutic drug monitoring for dose adaptation is of major interest for these patients, as the efficacy of ceftazidime seems to be directly related to its plasma concentration.

Population Pharmacokinetic (Pop-PK) Analysis of Torsemide in Healthy Korean Males Considering CYP2C9 and OATP1B1 Genetic Polymorphisms.

Torsemide is a diuretic drug used for several cardiovascular and chronic diseases. With regard to the clinical application of torsemide, studies on individualized pharmacotherapy and modeling that take variability in pharmacokinetics (PKs) within a population into account have been rarely reported. Thus, the objective of this study was to perform population pharmacokinetic (Pop-PK) modeling and to identify effective covariates that could explain the inter-individual variability (IIV) of torsemide PK. Pop-PK modeling for torsemide was performed based on serum concentration data obtained from 112 healthy Korean males and analysis of various genetic and physicochemical parameters. Modeling was performed with nonlinear mixed-effects (NLME) using Phoenix NLME. The finally developed model was fully verified. The model was also reconfirmed using NONMEM software. As a basic model, the PKs of torsemide within the population were well described by a two-compartment model reflecting the lag-time on oral absorption. According to the genetic polymorphisms of OATP1B1 and CYP2C9, significant associations were found in the V/F, CL/F, and CL2/F of torsemide. These were reflected as effective covariates in the final Pop-PK model of torsemide, resulting in an approximately 5–10% improvement in the model parameter IIV values. Considering that torsemide is a substrate for CYP2C9 and OATP1B1, it was important to search for genetic polymorphisms in CYP2C9 and OATP1B1 as covariates to explain the PK diversity of torsemide between individuals. The differences in CL/F and CL2/F between the phenotypes of CYP2C9 were approximately 36.5–51%. The difference in V/F between the phenotypes of OATP1B1 was approximately 41–64.6%. These results suggested that the phenotypes of CYP2C9 and OATP1B1 produced significant differences in torsemide PKs. Considering that CYP2C9 and OATP1B1 phenotypes as covariates affected different PK parameters of torsemide, it could be inferred that torsemide’s cell membrane permeation process by OATP1B1 and the metabolic process by CYP2C9 could independently affect each other in vivo without interplay. There was no significant difference in the parameter estimates between modeling software (Phoenix NLME vs. NONMEM). In this study, the torsemide PK variability between individuals was largely explained. In the future, individualized effective drug therapy of torsemide taking individual patient’s genotypes into account might become possible.

Inter-individual variability in pharmacokinetics and clinical features in pediatric patients with severe hemophilia A

IntroductionAs the most commonly used FVIII concentrate in China, the individualized pharmacokinetics (PK) and clinical outcomes of Kovaltry (BAY81-8973) are not fully investigated in this population. Materials and methodsPediatric patients with severe hemophilia A were enrolled in Beijing Children's Hospital. After a three-day washout, they received PK tests after a single-dose infusion of 50 IU/kg. The blood samples were collected with a six-point assay. One-stage-based activated partial thromboplastin time was used for FVIII activity. The PK parameters were generated by WinNonlin software. The bleeding rates were calculated by their routine therapy record. The ultrasound was used to evaluate their both sides of knees, elbows and ankles. ResultSixty-one boys with severe hemophilia A were enrolled and their median age was 5.73 years. Twenty-nine of them were blood group-O. Compared with blood group-O patients, those non-O patients showed longer t1/2 (15.26 vs. 13.03 h, P < 0.001) and reduced CL (3.04 vs. 3.66 mL/kg/h, P < 0.05). Patients with higher VWF:Ag level had longer half-life time (t1/2) (r = 0.60, P < 0.0001) and lower clearance (CL) (r = −0.45, P < 0.001). Patients with higher trough level showed decreased bleeding rates compared with those owning a trough level below 1 IU/dL (P < 0.05). In general, the zero bleeding rates raised with elevation of trough level. However, 20–30% of patients with low trough level (<1 IU/dL) also showed no bleeds and 10–20% of patients with high trough level (>5 IU/dL) still suffer bleeds. An inconsistency of 28% between joint bleeds and ultrasound evaluation was showed. ConclusionThis study revealed the great inter-individual variability in PK parameters, clinical bleeding phenotype and joint vulnerability, which all should be considered in treating hemophilia A.

Quantification of Venetoclax for Therapeutic Drug Monitoring in Chinese Acute Myeloid Leukemia Patients by a Validated UPLC-MS/MS Method.

Venetoclax has emerged as a breakthrough for treatment of leukemia with a wide interindividual variability in pharmacokinetics. Herein, a rapid, sensitive, and reliable UPLC-MS/MS method for quantification of venetoclax in plasma was developed and validated. The method was operated in the multiple-reaction monitoring (MRM) mode to detect venetoclax at m/z transition 868.5 > 321.0 and IS at 875.5 > 321.0, respectively. Protein precipitation prior to injection into the LC-MS/MS and the analyte was separated on an ACQUITY UPLC BEH C18 column by gradient elution with acetonitrile and 0.1% formic acid in water. Linear calibration curves were obtained in the range of 25–8000 ng/mL. The specificity, recovery, matrix effect, and stability also met the acceptance criteria of FDA guidance. The method was successfully applied to analyze plasma in acute myeloid leukemia (AML) patients. The peak plasma concentration (Cmax) of venetoclax in Chinese AML patient was 2966.0 ± 1595.0 ng/mL while the trough concentration (Cmin) was 1018.0 ± 729.4 ng/mL. Additionally, Cmax and Cmin showed a positive correlation with AST levels. Furthermore, Cmax was significantly higher in the older patients. The present method can be applied for TDM of venetoclax in treatment of hematological cancers.

Pharmacokinetics of Caffeine: A Systematic Analysis of Reported Data for Application in Metabolic Phenotyping and Liver Function Testing.

Caffeine is by far the most ubiquitous psychostimulant worldwide found in tea, coffee, cocoa, energy drinks, and many other beverages and food. Caffeine is almost exclusively metabolized in the liver by the cytochrome P-450 enzyme system to the main product paraxanthine and the additional products theobromine and theophylline. Besides its stimulating properties, two important applications of caffeine are metabolic phenotyping of cytochrome P450 1A2 (CYP1A2) and liver function testing. An open challenge in this context is to identify underlying causes of the large inter-individual variability in caffeine pharmacokinetics. Data is urgently needed to understand and quantify confounding factors such as lifestyle (e.g., smoking), the effects of drug-caffeine interactions (e.g., medication metabolized via CYP1A2), and the effect of disease. Here we report the first integrative and systematic analysis of data on caffeine pharmacokinetics from 141 publications and provide a comprehensive high-quality data set on the pharmacokinetics of caffeine, caffeine metabolites, and their metabolic ratios in human adults. The data set is enriched by meta-data on the characteristics of studied patient cohorts and subjects (e.g., age, body weight, smoking status, health status), the applied interventions (e.g., dosing, substance, route of application), measured pharmacokinetic time-courses, and pharmacokinetic parameters (e.g., clearance, half-life, area under the curve). We demonstrate via multiple applications how the data set can be used to solidify existing knowledge and gain new insights relevant for metabolic phenotyping and liver function testing based on caffeine. Specifically, we analyzed 1) the alteration of caffeine pharmacokinetics with smoking and use of oral contraceptives; 2) drug-drug interactions with caffeine as possible confounding factors of caffeine pharmacokinetics or source of adverse effects; 3) alteration of caffeine pharmacokinetics in disease; and 4) the applicability of caffeine as a salivary test substance by comparison of plasma and saliva data. In conclusion, our data set and analyses provide important resources which could enable more accurate caffeine-based metabolic phenotyping and liver function testing.

Factors influencing methotrexate and methotrexate polyglutamate in patients with rheumatoid arthritis: a systematic review of population pharmacokinetics.

Low dose methotrexate (MTX) is commonly used in the treatment of rheumatoid arthritis. The clinical effect is mediated by its metabolite, methotrexate polyglutamate (MTX-PGn). The drug exhibits high interindividual pharmacokinetic variability and the optimal MTX dose is different among individuals. Thus, several MTX population pharmacokinetic (PopPK) models were developed to characterize factors affecting MTX pharmacokinetic variability. This review summarizes significant predictors for MTX pharmacokinetics and identifies knowledge gaps to be further examined. A total of 359 articles were identified from a systematic search of four databases: PubMed, Science Direct, and CINAHL Complete. Of these eight studies were included. Most studies investigated influential factors on MTX pharmacokinetics, but information on MTX-PGn is limited, with only one study performing a parent-metabolite (MTX-PG3) model. MTX pharmacokinetics was described using a two-compartment model with first-order elimination in most studies, with the MTX clearance ranging from 6.94 to 12.39L/h. Significant predictors influencing MTX clearance included weight, creatinine clearance, sex, OATP1B3 polymorphism, and MTX multiple dosing. While body mass index and red blood cell counts were significant predictors for MTX-PG3 clearance. Providing that MTX-PGn plays a crucial role in clinical effect, further studies should determine other factors affecting MTX-PGn as well as its relationship with clinical response.

Ganciclovir Pharmacokinetics and Individualized Dosing Based on Covariate in Lung Transplant Recipients.

The aim of this prospective study was to evaluate the pharmacokinetics of ganciclovir in lung transplant recipients, to explore its covariates, and to propose an individualized dosing regimen. Ganciclovir was administered according to the protocol in a standardized intravenous dose of 5 mg/kg twice daily. Serum ganciclovir concentrations were monitored as a trough and at 3 and 5 h after dosing. Individual ganciclovir pharmacokinetic parameters were calculated in a two-compartmental pharmacokinetic model, while regression models were used to explore the covariates. Optimal loading and maintenance doses were calculated for each patient. In lung transplant recipients (n = 40), the median (IQR) ganciclovir total volume of distribution and clearance values were 0.65 (0.52–0.73) L/kg and 0.088 (0.059–0.118) L/h/kg, respectively. We observed medium-to-high inter-individual but negligible intra-individual variability in ganciclovir pharmacokinetics. The volume of distribution of ganciclovir was best predicted by height, while clearance was predicted by glomerular filtration rate. Bodyweight-normalized clearance was significantly higher in patients with cystic fibrosis, while distribution half-life was reduced in this subgroup. On the basis of the observed relationships, practical nomograms for individualized ganciclovir dosing were proposed. The dosing of ganciclovir in patients with cystic fibrosis requires special caution, as their daily maintenance dose should be increased by approximately 50%.