Population pharmacokinetics and Bayesian estimation of tacrolimus exposure in paediatric liver transplant recipients.

AIMS: The objectives of this study were to develop a population pharmacokinetic (PopPK) model for tacrolimus in paediatric liver transplant patients and determine optimal sampling strategies to estimate tacrolimus exposure accurately. METHODS: Twelve hour intensive pharmacokinetic profiles from 30 patients (age 0.4-18.4 years) receiving tacrolimus orally were analysed. The PopPK model explored the following covariates: weight, age, sex, type of transplant, age of liver donor, liver function tests, albumin, haematocrit, drug interactions, drug formulation and time post-transplantation. Optimal sampling strategies were developed and validated with jackknife. RESULTS: A two-compartment model with first-order absorption and elimination and lag time described the data. Weight was included on all pharmacokinetic parameters. Typical apparent clearance and central volume of distribution were 12.1 l h(-1) and 31.3 l, respectively. The PopPK approach led to the development of optimal sampling strategies, which allowed estimation of tacrolimus pharmacokinetics and area under the concentration­time curve (AUC) on the basis of practical sampling schedules (three or four sampling times within 4 h) with clinically acceptable prediction error limit. The mean bias and precision of the Bayesian vs. reference (trapezoidal) AUCs ranged from -2.8 to -1.9% and from 7.4 to 12.5%, respectively. CONCLUSIONS: The PopPK of tacrolimus and empirical Bayesian estimates represent an accurate and convenient method to predict tacrolimus AUC(0-12) in paediatric liver transplant recipients, despite high between-subject variability in pharmacokinetics and patient demographics. The developed optimal sampling strategies will allow the undertaking of prospective trials to define the tacrolimus AUC-based therapeutic window and dosing guidelines in this population.

Novel population pharmacokinetic method compared to the standard noncompartmental approach to assess bioequivalence of iron gluconate formulations.

PURPOSE: Iron-containing products are atypical in terms of their pharmacokinetic properties because iron is only removed by plasma sampling and is non-linear. This study aims to present a novel way of assessing the relative bioavailability of two sodium ferric gluconate complex (SFGC) formulations and compare this approach to a standard previously published noncompartmental approach. METHODS: Data were from open-label, randomized, single-dose studies (Study 1 was parallel whereas Study 2 was crossover). Subjects with low but normal iron levels were infused IV SFGC in sucrose by GeneraMedix Inc. and/or Ferrlecit ® Injection (Watson Laboratories Inc.). In Study 1 (n=240), 125 mg was infused over 10 minutes. In Study 2 (n=29), 62.5 mg was infused over 30 minutes. Samples were assayed for total iron (TI) and transferrin-bound iron (TBI) over 36 hours (Study 1) or 72 hours (Study 2) post-dose. Studies 1 and 2 used standard noncompartmental analysis. Study 2 also used population PK (PPK) analyses with ADAPT 5®. The final model predicted SFGC area-under-the-curve (AUCpred) and maximal concentration (Cmaxpred). Analyses of variance was conducted on ln-transformed PK parameters. Ratios of means and 90% confidence intervals (CIs) were estimated. Bioequivalence was demonstrated if values were within 80-125%. RESULTS: For Study 1, ratios and 90% CIs for TI baseline-corrected Cmax and AUC0-36 were 100.4 (96.5 - 104.5) and 99.7 (94.2 - 105.5). For TBI, results for TI baseline-corrected Cmax and AUC0-36 were 86.8 (82.7 - 91.1) and 92.4 (85.6 - 99.7). For Study 2, a multi-compartmental model simultaneously described the PK of TI, TBI and SFGC. Ratios and 90% CIs for SFGC Cmaxpred and AUCpred were 89.9 (85.9 - 94.0) and 89.7 (85.7 - 93.9), while ratios and 90% CI obtained from the noncompartmental analysis of Study 2 did not meet BE criteria because of low power. CONCLUSIONS: Both the standard and PPK modeling approach suggested bioequivalence between the iron products. However, with the PPK method, less subjects were required to meet study objectives compared to the standard noncompartmental approach which required considerably more subjects (29 vs 240).

Limited sampling strategies for monitoring tacrolimus in pediatric liver transplant recipients.

OBJECTIVE: To develop and validate limited sampling strategies (LSSs) for tacrolimus in pediatric liver transplant recipients. METHODS: Thirty-six 12-hour pharmacokinetic profiles from 28 pediatric liver transplant recipients (0.4-18.5 years) were collected. Tacrolimus concentrations were measured by immunoassay and area under the curve (AUC0-12) was determined by trapezoidal rule. LSSs consisting of 1, 2, 3, or 4 concentration-time points were developed using multiple regression analysis. Eight promising models (2 per category) were selected based on the following criteria: r2 ≥ 0.90, inclusion of trough concentration (C0), and time points within 4 hours postdose. The predictive performance of these LSSs was evaluated in an independent set of data by measuring the mean prediction error and the root mean squared prediction error. RESULTS: Five models including 2-4 time points predicted AUC0-12 with a ±15% error limit. Bias (mean prediction error) and precision (root mean squared prediction error) of LSS involving C0, C1, and C4 (AUCpredicted = 9.30 + 3.69 × C0 + 2.19 × C1 + 4.69 × C4) were -4.98% and 8.29%, respectively. Among single time point LSSs, the model using C0 had a poor correlation with AUC0-12 (r2 = 0.53), whereas the one with C4 had the highest correlation with tacrolimus exposure (r2 = 0.84). CONCLUSIONS: Trough concentration is a poor predictor of tacrolimus AUC0-12 in pediatric liver transplant recipients. However, LSSs using 2-4 concentration-time points obtained within 4 hours postdose provide a reliable and convenient method to predict tacrolimus exposure in this population. The proposed LSSs represent an important step that will allow the undertaking of prospective trials aiming to better define tacrolimus target AUC in pediatric liver transplant recipients and to determine whether AUC-guided monitoring is superior to C0-based monitoring in terms of efficacy and safety.

Increased risk of myocardial infarction associated with angiotensin-converting enzyme gene polymorphism is age dependent.

The angiotensin-converting enzyme (ACE) gene is a candidate genetic locus for coronary artery disease (CAD). Studies investigating the relationship between the ACE-insertion/deletion (I/D) gene polymorphism and myocardial infarction (MI) have been inconsistent. The authors hypothesized that age may be an important modulating factor in this relationship. ACE-I/D allele and genotype distribution was determined in 3 groups: 104 men with a first MI at a young age (≤45 years old), 271 healthy young men (≤30 years old), and 28 healthy elderly men (>65 years old). All participants were French descendants from Quebec City, Canada. Frequency distribution of the ACE alleles and genotypes was similar among the healthy young, the healthy elderly, and the MI patients (P > .05). However, when considering the age at the time of the MI (≤40, ≤35, or ≤30 years old), a significant age-dependent effect with the prevalence of the ACE-DD genotype was found, as it increased by 22%, 61%, and 157%, respectively, compared with the healthy young group (P < .05). Similar observations were obtained versus the healthy elderly men (P < .05). The ACE-I/D polymorphism seems to be a genetic risk factor for MI in young men and becomes an important modulator of MI risk at a young age.

Population pharmacokinetics of intravenous pantoprazole in paediatric intensive care patients.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: The use of intravenous pantoprazole, a proton pump inhibitor, has been increasing in the paediatric intensive care unit. Despite this increased use, data on the disposition of intravenous pantoprazole in paediatric intensive care patients are very scarce. WHAT THIS STUDY ADDS: Our population approach has determined the pharmacokinetic parameters of intravenous pantoprazole in paediatric intensive care patients and the relative importance of factors influencing its disposition. Pantoprazole clearance was significantly influenced by developmental changes and by the presence of systemic inflammatory syndrome, hepatic dysfunction and CYP2C19 inhibitors. AIMS: To characterize the pharmacokinetics of intravenous pantoprazole in a paediatric intensive care population and to determine the influence of demographic factors, systemic inflammatory response syndrome (SIRS), hepatic dysfunction and concomitantly used CYP2C19 inducers and inhibitors on the drug's pharmacokinetics. METHODS: A total of 156 pantoprazole concentration measurements from 20 patients (10 days to 16.4 years of age) at risk for or with upper gastrointestinal bleeding, who received pantoprazole doses ranging from 19.9 to 140.6 mg/1.73 m(2)/day, were analysed using a population pharmacokinetic approach (nonmem program). RESULTS: The best structural model for pantoprazole was a two-compartment model with zero order infusion and first-order elimination. Body weight, SIRS, age, hepatic dysfunction and presence of CYP2C19 inhibitors were significant covariates affecting clearance (CL), accounting for 75% of interindividual variability. Only body weight significantly influenced central volume of distribution (V(c)). In the final population model, the estimated CL and V(c) were 5.28 l h(-1) and 2.22 l, respectively, for a typical 5-year-old child weighing 20 kg. Pantoprazole CL increased with weight and age, whereas the presence of SIRS, CYP2C19 inhibitors and hepatic dysfunction, when present separately, significantly decreased pantoprazole CL by 62.3, 65.8 and 50.5%, respectively. For patients aged between 6 months and 5 years without SIRS, CYP2C19 inhibitor or hepatic dysfunction, the predicted pantoprazole CL is faster than that reported in adults. CONCLUSION: These results provide important information for physicians regarding selection of a starting dose and dosing regimens of pantoprazole for paediatric intensive care patients based on factors frequently encountered in this population.

Inhibitory effects of propafenone on the pharmacokinetics of caffeine in humans.

CYP1A2 is involved in the metabolism of both caffeine and propafenone, a class Ic antiarrhythmic agent. Despite the widespread consumption of caffeine, drug-drug interactions with this agent are often overlooked. This study investigated effects of propafenone on the pharmacokinetics of caffeine. Eight healthy volunteers were included in our study. A total of 300 mg of caffeine was given on 2 occasions, once alone and once during the coadministration of 300 mg propafenone. Serial blood samples were collected and pharmacokinetic parameters were estimated using a population pharmacokinetic approach. A one-compartment PK model with first-order absorption and elimination described plasma concentration profiles. Concomitant administration of propafenone decreased caffeine oral clearance from 8.3 +/- 0.9 L/h to 5.4 +/- 0.7 L/h (P < 0.05). Elimination half-life of caffeine was also increased 54% by propafenone. One of our volunteers was a poor metabolizer of CYP2D6. Concomitant administration of propafenone to this volunteer caused the greatest increase in caffeine plasma concentrations. These results support the concept of competitive inhibition between propafenone and caffeine. Our results suggest that propafenone causes significant inhibition of CYP1A2 activity leading to a decrease in the clearance of caffeine. Caffeine has intrinsic proarrhythmic effects; thus, its coadministration with an antiarrhythmic agent such as propafenone should be used with caution, especially in patients with poor CYP2D6 activity.

Multilocus genetic interactions and response to efavirenz-containing regimens: an adult AIDS clinical trials group study.

OBJECTIVE: For the HIV-1 reverse transcriptase inhibitor efavirenz, variant drug transporter gene ABCB1 may predict virologic response but not plasma efavirenz exposure. Conversely, variant drug metabolizing enzyme gene CYP2B6 predicts greater plasma efavirenz exposure but not virologic response. We examined whether long-term responses to efavirenz, and/or plasma efavirenz exposure, are better predicted by multilocus genetic interactions than by individual polymorphisms. MATERIALS AND METHODS: We studied antiretroviral-naïve study participants randomized to receive efavirenz (with or without nelfinavir) plus two nucleoside analogues in study ACTG 384, and who had DNA available for analysis. Participants were followed up for up to 3 years. Nine single nucleotide polymorphisms in ABCB1, CYP2B6, CYP3A4, CYP3A5 and CYP2C19 were identified. Gene-gene interactions were identified using multifactor dimensionality reduction. RESULTS: Among 340 efavirenz recipients, higher efavirenz AUC24 h values were associated with a single locus model involving CYP2B6 516G>T (73% accuracy; P<0.001). This was also the best model among blacks (69% accuracy; P<0.001), whereas among whites the best model involved a gene-gene interaction between CYP2B6 516G>T and ABCB1 2677G>T (82% accuracy, P<0.001). Among 155 participants who received efavirenz without nelfinavir, virologic failure was associated with a two-locus interaction between ABCB1 2677G>T and CYP2B6 516G>T (65% accuracy, P<0.001). Toxicity failure was best predicted by an interaction between ABCB1 2677G>T and ABCB1 3435C>T (71% accuracy, P<0.001). CONCLUSIONS: Multilocus genetic interactions between variant drug metabolism and transporter genes may predict efavirenz pharmacokinetics and treatment responses. This finding may have implications for better individualizing antiretroviral therapy.

A non-linear mixed effect dynamic model incorporating prior exposure and adherence to treatment to describe long-term therapy outcome in HIV-patients.

Long term therapy with antiretroviral agents in HIV-infected patients often result in failure to suppress the virus load. Imperfect adherence to prescribed antiviral drugs is an important factor explaining the resurgence of virus. A better understanding of the factors responsible for the virological failure is important for the development of new treatment strategies. Many complex non-linear models have been developed to describe and simulate the dynamics of HIV-1 virus. Those complicated viral dynamic models have not been used in clinical trials to estimate HIV dynamics parameters, due to their complexity, until the recent development of simplification and approximation techniques. The estimation of the parameters associated with the dynamics from real data has been mostly limited to linearized models that can only explain the decay (suppression) of the virus following antiviral treatment. Moreover, no complete characterization of typical clinical data in terms of inter-subject variability and identification of important covariates effecting HIV-1 dynamics has been attempted. The objective of our paper was to develop a hierarchical non-linear mixed effect model characterizing inter-subject variability in the long-term response to treatment of HIV-1 RNA, and show how the model can be used to quantify the effect of important covariates, such as physiological variables, adherence to treatment or previous exposure to treatment, on the dynamics of HIV-1 RNA. As an example we report the analysis of AIDS clinical trial data from AACTG 398, which shows that patients with previous exposure to treatment show faster death rates for HIV-1, and that higher adherence to treatment is associated with lower reproductive ratio.

Modeling and simulation of adherence: approaches and applications in therapeutics.

Partial adherence with a prescribed or randomly assigned dose gives rise to unintended variability in actual drug exposure in clinical practice and during clinical trials. There are tremendous costs associated with incomplete and/or improper drug intake-to both individual patients and society as a whole. Methodology for quantifying the relation between adherence, exposure and drug response is an area of active research. Modeling and statistical approaches have been useful in evaluating the impact of adherence on therapeutics and in addressing the challenges of confounding and measurement error which arise in this context. This paper reviews quantitative approaches to using adherence information in improving therapeutics. It draws heavily on applications in the area of HIV pharmacology.

Pharmacogenetics of long-term responses to antiretroviral regimens containing Efavirenz and/or Nelfinavir: an Adult Aids Clinical Trials Group Study.

BACKGROUND: Efavirenz and nelfinavir are metabolized by cytochrome P-450 (CYP) 2B6 and CYP2C19, respectively, with some involvement by CYP3A. Nelfinavir is a substrate for P-glycoprotein, which is encoded by MDR1. The present study examined associations between genetic variants and long-term responses to treatment. METHODS: Adult AIDS Clinical Trials Group study 384 randomized antiretroviral-naive subjects to receive efavirenz and/or nelfinavir plus 2 nucleoside analogues, with follow-up lasting up to 3 years. Population pharmacokinetics were estimated from a nonlinear mixed-effects model. Polymorphisms in CYP2B6, CYP2C19, CYP3A4, CYP3A5, and MDR1 were characterized. RESULTS: The 504 participants in the genetic study included 340 efavirenz recipients and 348 nelfinavir recipients (184 of the 504 participants received both efavirenz and nelfinavir). Of the participants, 49% were white, 31% were black, and 19% were Hispanic. Plasma exposure to efavirenz and nelfinavir in each population was significantly associated with the polymorphisms CYP2B6 516G-->T and CYP2C19 681G-->A, respectively. Among efavirenz recipients, the MDR1 position 3435 TT genotype was associated with decreased likelihood of virologic failure and decreased emergence of efavirenz-resistant virus but not with plasma efavirenz exposure. Among nelfinavir recipients, a trend toward decreased virologic failure was associated with the polymorphism CYP2C19 681G-->A. CONCLUSIONS: Genetic variants predict plasma exposure to efavirenz and nelfinavir, and they may predict virologic failure and/or emergence of drug-resistant virus. These associations with treatment responses must be validated in other studies.

Application and impact of population pharmacokinetics in the assessment of antiretroviral pharmacotherapy.

Population pharmacokinetics has been an important technique used to explore and define relevant sources of variation in drug exposure and response in patient populations. This has been especially true in the area of antiretroviral therapy where the assurance of adequate and sustained drug exposure of multiple agents is highly correlated with therapeutic success. Population pharmacokinetic analyses across the four drug classes and 20 US FDA-approved products used to treat HIV have been published to date. The published reports were predominantly based on actual clinical trials conducted in HIV-infected patients with one or more agents administered. Modelling and simulation approaches have been used in the evaluation of antiretroviral agent outcomes incorporating problematic design and analysis factors such as sparse plasma sampling, data imbalance and censored data. Additional benefits of population modelling approaches applied to the investigation of antiretroviral agents include the ability to assess dosing compliance, understanding and quantifying drug-drug interactions in order to select dosing regimens and the screening of new drug candidates. Pharmacokinetic/pharmacodynamic models have been used to characterise the relationship between drug exposure and virological and immunological response, and to predict clinical outcome. These models offer the best opportunity for individualising and optimising patient therapy, particularly when adjusted for adherence/compliance. The impact of population pharmacokinetics in the area of antiretroviral therapy can be directly assessed by its role in the validation of surrogate markers such as viral RNA load, therapeutic drug monitoring and the management of individual patient outcomes via exposure-toxicity relationships. Each of these population pharmacokinetic outcomes has contributed to the current regulatory environment, specifically in the area of accelerated approval of new antiretroviral agents.

Effects of ciprofloxacin on the stereoselective disposition of mexiletine in man.

Mexiletine is extensively metabolized in man, with less than 10% of the dose being excreted unchanged in urine. Clinical drug-drug interaction studies as well as in vitro drug metabolism studies suggest that CYP1A2, in addition to CYP2D6, is involved in the metabolism of mexiletine in man. Therefore, the objective of the study was to determine whether potential inhibition of CYP1A2 by the quinolone antibiotic agent ciprofloxacin would alter the stereoselective disposition of mexiletine. Nineteen healthy men (10 smokers and 9 nonsmokers) received a single 200-mg oral dose of racemic mexiletine hydrochloride on 2 occasions: once alone and once during concomitant administration of ciprofloxacin 750 mg BID (starting 3 days before and up to 2 days after the administration of mexiletine). Serial blood and urine samples were collected for 48 hours, and pharmacokinetic parameters were derived. Total clearances of R-(-)- and S-(+)-mexiletine were 42% and 63% higher in smokers compared with nonsmokers (P < 0.05). This observation is in agreement with increased clearance of mexiletine under conditions of increased CYP1A2 activity. On the other hand, ciprofloxacin administration only marginally decreased R-(-)- and S-(+)-mexiletine clearances (2 to 5 L/h; P < 0.05) secondary to a decrease in mexiletine nonrenal clearance. In conclusion, the increase in mexiletine nonrenal clearance in smokers and its decrease during the combined administration of ciprofloxacin confirm the role of CYP1A2 in the overall clearance of the drug. Nevertheless, results obtained in this study suggest that no major drug interaction is to be expected during the concomitant administration of ciprofloxacin and mexiletine in patients.

Population pharmacokinetics and pharmacodynamics of efavirenz, nelfinavir, and indinavir: Adult AIDS Clinical Trial Group Study 398.

The present population pharmacokinetic (PK) and pharmacodynamic (PD) study modeled the effects of covariates including drug adherence and the coadministration of protease inhibitors (PIs) on the pharmacokinetics of efavirenz (EFV) and the relationship between EFV exposure and virological failure in patients who failed initial PI treatment in Adult AIDS Clinical Trial Group (AACTG) study 398. We also report on the population PKs of the PIs nelfinavir (NFV) and indinavir (IDV). AACTG study 398 patients received EFV, amprenavir, adefovir dipivoxil, and abacavir and were randomized to take, in addition, one of the following: NFV, IDV, saquinavir (SQV), or placebo. The PK databases consisted of 531 EFV concentrations (139 patients), 219 NFV concentrations (75 patients), and 66 IDV concentrations (11 patients). Time to virological failure was ascertained for all patients in the PK databases. PK data were fit with a population PK model that assumed exclusive hepatic elimination (the well-stirred model). Notable findings with respect to EFV PK and PD are as follows. (i) The hepatic clearance of EFV is unaltered by NFV, IDV, or SQV coadministration. (ii) The hepatic clearance of EFV appears to be 28% higher in white non-Hispanics than in African Americans and Hispanics (P = 0.03). (iii) Higher adherence scores (as measured with the Medication Event Monitoring System) are associated with marginally increased levels of exposure to EFV. (iv) In patients with no prior experience with nonnucleoside reverse transcriptase inhibitors (NNRTIs), a given percent increase in the oral clearance (CL/F) of EFV is associated with a greater percent increase in the hazard of virological failure (P < 0.0003). Among NNRTI-experienced patients, however, hazard is relatively uncorrelated with EFV CL/F.

Effect of coadministration of nelfinavir, indinavir, and saquinavir on the pharmacokinetics of amprenavir.

OBJECTIVE: Pharmacokinetic interactions are expected when human immunodeficiency virus (HIV) protease inhibitors are coadministered because many are both substrates for and inhibitors of CYP3A4. The goal of this model-based pharmacokinetic analysis was to describe the differences observed in amprenavir pharmacokinetics among treatment arms in the Adult AIDS Clinical Trial Group (AACTG) study protocol 398 and to propose mechanisms to account for them. METHODS: One hundred seventy-six HIV-positive subjects receiving 1200 mg amprenavir twice daily as part of AACTG protocol 398 were included in the pharmacokinetic study. All patients also received background medications efavirenz, adefovir dipivoxil, and abacavir and, depending on the study arm, placebo or one of the following protease inhibitors: nelfinavir, indinavir, or saquinavir. A population pharmacokinetic model was fitted to a total of 565 amprenavir concentration measurements. The blood samples for concentration measurements were drawn at week 2 (12-hour pharmacokinetic study, approximately 7 samples per study; 46 patients) and at week 24 (6-hour pharmacokinetic study, approximately 5 samples per study; 10 patients). In addition, samples were collected at 1 or more follow-up visits (population pharmacokinetic study, 1 to 3 occasions per patient; 150 patients). RESULTS AND CONCLUSION: Amprenavir intrinsic clearance was significantly reduced relative to placebo by nelfinavir (-41%) and indinavir (-54%) but not by saquinavir. The absolute magnitude of amprenavir intrinsic clearance suggests that CYP3A4 inhibition by nelfinavir and indinavir is balanced by enzymatic induction in the presence of the background drug(s), most likely efavirenz. Amprenavir intrinsic clearance apparently increases by more than 30% between weeks 2 and 24, possibly because of the time course of CYP3A4 induction.