Evaluation of covariate effects using forest plots and introduction to the coveffectsplot R package.

The current tutorial describes why forest plots are needed for an effective communication of covariates effects, how they are constructed, and how they should be presented. Simulation-based methodologies allowing the user to evaluate the marginal impact of changing one covariate at a time or by considering the joint effects of correlated covariates are introduced along with graphical tools for an optimal assessment of the covariate effects. The R package coveffectsplot and an associated R Shiny application are provided to facilitate the design and construction of forest plots for the visualization of covariate effects. All codes and materials are available on a public Github repository.

Power calculations for cluster randomized trials (CRTs) with right-truncated Poisson-distributed outcomes: a motivating example from a malaria vector control trial.

BACKGROUND: Cluster randomized trials (CRTs) are increasingly used to study the efficacy of interventions targeted at the population level. Formulae exist to calculate sample sizes for CRTs, but they assume that the domain of the outcomes being considered covers the full range of values of the considered distribution. This assumption is frequently incorrect in epidemiological trials in which counts of infection episodes are right-truncated due to practical constraints on the number of times a person can be tested. METHODS: Motivated by a malaria vector control trial with right-truncated Poisson-distributed outcomes, we investigated the effect of right-truncation on power using Monte Carlo simulations. RESULTS: The results demonstrate that the adverse impact of right-truncation is directly proportional to the magnitude of the event rate, λ, with calculations of power being overestimated in instances where right-truncation was not accounted for. The severity of the adverse impact of right-truncation on power was more pronounced when the number of clusters was ≤30 but decreased the further the right-truncation point was from zero. CONCLUSIONS: Potential right-truncation should always be accounted for in the calculation of sample size requirements at the study design stage.

Population Pharmacokinetic/Pharmacodynamic Modeling of O-Desmethyltramadol in Young and Elderly Healthy Volunteers.

BACKGROUND: Age-related changes in the concentration-effect relationship of (+)-O-desmethyl-tramadol [(+)-ODM], tramadol's active metabolite, are not documented in the elderly. OBJECTIVE: The objective of this study was to characterize, in elderly and young subjects, the (+)-ODM pharmacokinetic and pharmacodynamic relationship to examine the effect of age after single-dose administration of tramadol 200 mg extended-release tablets. METHODS: A population analysis of a double-blind, randomized, placebo-controlled, two-period cross-over study including 13 elderly (aged ≥75 years) subjects with mild renal insufficiency and 16 young (aged 18-40 years) subjects was conducted. For 48 h post-dose, blood samples were collected and pain tolerance thresholds measured using an electrically stimulated pain model. A pharmacokinetic/pharmacodynamic model incorporating a one-compartment pharmacokinetic model for (+)-ODM parameterized with first-order formation rate, clearance (CL/fm), volume of distribution (V/fm) and a sigmoid maximum effect (Emax) model incorporating baseline (E0) and placebo effect was used. RESULTS: Maximum plasma concentrations of (+)-ODM occurred later and plasma concentrations declined more slowly in the elderly than in young subjects. In the elderly, V/fm was 76% larger and CL/fm 16% slower. Baseline (E0) and sensitivity (C50) for pain tolerance were similar between young and elderly subjects. However, the Emax parameter was 2.5 times higher in the elderly and maximum possible treatment-related effect was 169 (135-221) in the young and 194 (149-252) in the elderly; that is, 15% higher in the elderly. CONCLUSIONS: This exploratory analysis suggests that age-related differences exist in the distribution and elimination of (+)-ODM, including a 76% larger distribution outside the central compartment and 16% slower clearance of (+)-ODM. These pharmacokinetic changes are associated with a 15% higher maximum possible treatment-related effect and carry the potential for greater efficacy but also the potential for increased side effects at the same dose in elderly subjects. Clinicaltrials.gov identifier: NCT02329561.

Evaluation of an Experimental Pain Model by Noncompartmental Analysis of Results from a Randomized Placebo Controlled Trial.

BACKGROUND: Understanding analgesic pharmacodynamics (PD) in the elderly is key to optimising pain management. Electrically stimulated pain models (ESPM) permit assessment of pain responses in humans. C and A-delta sensory fibres convey pain and respond to low frequency electrical stimulus (5 and 250 Hz, respectively). Human research suggests pain tolerance threshold (PTT) is similar or decreases with age. OBJECTIVES: To determine whether an ESPM is able to detect a difference in PTT in elderly (>/= 75 years) and young (20-40 years) subjects after single dose administration of a placebo and tramadol, a low potency analgesic. STUDY DESIGN: Two-cohort, randomized, placebo-controlled, cross-over study. METHODS: A noncompartmental analysis of data at 17 timepoints on 5 Hz and 250 Hz PTT over 24 h. RESULTS: Young (16) and elderly (13) patients showed similar baseline (E0) PTT between active and placebo both overall and by age group in both frequencies. Net drug effect took into account negative and positive changes from E0. In the elderly, net peak effect on PTT produced by active treatment was significantly greater for both 5 Hz (34%) and 250 Hz (30%). Net area under the 24-h effect-time curve during active treatment was significantly higher for both 5 Hz (163 %) and 250 Hz (175%) stimulations in the elderly. No clinically significant difference was observed in the young. LIMITATIONS: High variability in young subjects, despite efforts to remove outliers limited our ability to draw conclusions in that age group. Generalizability of results obtained from an experimental pain model in volunteers to treatment of elderly patients may be limited. CONCLUSION: ESPM can detect a difference for pain tolerance threshold between placebo and tramadol administration in the elderly. Although both 5 Hz and 250 Hz stimulations can detect a difference, the effect size for 5 Hz is larger and seems more precise and reliable, particularly in the elderly. KEY WORDS: Electrical pain model, elderly, geriatric, tramadol, placebo, opioid, area under the effect curve, noncompartmental analysis.

Total Kidney Volume Is a Prognostic Biomarker of Renal Function Decline and Progression to End-Stage Renal Disease in Patients With Autosomal Dominant Polycystic Kidney Disease.

INTRODUCTION: Autosomal dominant polycystic kidney disease is the most common hereditary kidney disease. TKV is a promising imaging biomarker for tracking and predicting the natural history of autosomal dominant polycystic kidney disease. The prognostic value of TKV was evaluated, in combination with age and eGFR, for the outcomes of 30% decline in eGFR and progression to ESRD. Observational data including 2355 patients with TKV measurements were available. METHODS: Multivariable Cox models were developed to assess the prognostic value of age, TKV, height-adjusted TKV, eGFR, sex, race, and genotype for the probability of a 30% decline in eGFR or ESRD. RESULTS: TKV was the most important prognostic term for 30% decline in eGFR in autosomal dominant polycystic kidney disease patients with and without preserved baseline eGFR. For a 40-year-old subject with preserved eGFR (70 ml/min per 1.73 m2), the adjusted hazard ratios for a 30% decline in eGFR were 1.86 (95% CI, 1.65-2.10) for a 2-fold larger TKV (600 vs. 1200 ml) and 2.68 (95% CI, 2.22-3.24) for a 3-fold larger TKV (600 vs. 1800 ml), respectively. Hazard ratios for progression to ESRD for 2- and 3-fold larger TKV were 1.72 (95% CI, 1.49-1.99) and 2.36 (95% CI, 1.88-2.97), respectively. DISCUSSION: The capability to predict 30% decline in eGFR is a novel aspect of this study. TKV was formally qualified, both by FDA and EMA, as a prognostic enrichment biomarker for selecting patients at high risk for a progressive decline in renal function for inclusion in interventional clinical trials.

A Drug Development Tool for Trial Enrichment in Patients With Autosomal Dominant Polycystic Kidney Disease.

INTRODUCTION: Total kidney volume (TKV) is a promising imaging biomarker for tracking and predicting the natural history of patients with autosomal dominant polycystic kidney disease. METHODS: A drug development tool was developed by linking longitudinal TKV measurements to the probability of a 30% decline of estimated glomerular filtration rate (eGFR) or end-stage renal disease. Drug development tools were developed based on observational data collected over multiple decades for an eGFR decline and end-stage renal disease in 641 and 866 patients with autosomal dominant polycystic kidney disease, respectively. RESULTS: The statistical association between predicted TKV at the time of a 30% decline of eGFR and that at the time of end-stage renal disease were both highly significant (P < 0.0001). The drug development tool was applied to demonstrate the utility of trial enrichment according to prespecified baseline TKV, age, and eGFR as enrollment criteria in hypothetical clinical trials. Patients with larger TKV (≥1000 ml) displayed steeper slopes of hazard, which translated into a higher risk of a 30% decline of eGFR within each baseline age (< or ≥40 years) or baseline eGFR (< or ≥50 ml/min per 1.73 m2) subgroups. DISCUSSION: These results suggest that, when eGFR is preserved, patients with larger TKV are more likely to progress to a 30% decline of eGFR within the course of a clinical trial, whereas eGFR and age displayed limited predictive value of disease progression in early disease. Pharmaceutical sponsors and academic investigators are encouraged to prospectively employ the above drug development tool to optimize trial designs in patients with autosomal dominant polycystic kidney disease.

Population pharmacokinetics and exposure-response of trametinib, a MEK inhibitor, in patients with BRAF V600 mutation-positive melanoma.

PURPOSE: To characterize the pharmacokinetics of oral trametinib, a first in class MEK inhibitor, identify covariates, and describe the relationship between exposure and clinical effects in patients with BRAF V600 metastatic melanoma. EXPERIMENTAL DESIGN: Trametinib concentrations obtained in three clinical studies were included in the population pharmacokinetic analysis. Trametinib 2 mg once daily was administered in the Phase 2 and 3 studies. The impact of exposure [trough (C min) or average concentration] on response rates and progression-free survival (PFS) was examined. RESULTS: Plasma concentrations (n = 3120) obtained in 493 patients were described using a two-compartment model. Trametinib oral clearance was lower in women relative to men (1.26-fold) and increased with body weight. There was no significant effect of age, mild or moderate renal impairment, or mild hepatic impairment on oral clearance. Between-subject variability was low (24 %). The number of responders was consistent across median exposure range, although tended to be lower at trough concentration <10 ng/mL. Disease stage was found to be a significant predictor of response with a lower response rate in patients with disease stage of M1c. Lactate dehydrogenase was significant in the analysis of PFS. Patients with observed C min above the median had longer PFS than those below median based on Phase 2 study (median 10.6 ng/mL), while the effect of exposure was not statistically significant in the Phase 3 study (median 13.6 ng/mL). CONCLUSIONS: No dosage adjustments are required with any of the covariates tested. Clinical efficacy was associated with trametinib trough concentrations greater than 10 ng/mL.

Pharmacokinetics of Tramadol and O-Desmethyltramadol Enantiomers Following Administration of Extended-Release Tablets to Elderly and Young Subjects.

BACKGROUND: Tramadol is frequently used in geriatric patients; however, pharmacokinetic (PK) publications on tramadol and O-desmethyltramadol (ODM) in elderly patients are rare. OBJECTIVE: Our objective was to characterize the PK of tramadol and ODM, including absorption processes and covariates for tramadol, in elderly and young subjects after single-dose administration of 200-mg extended-release tablets. METHODS: We conducted a PK study in 15 elderly (aged ≥75 years) subjects with mild renal insufficiency and 20 young (18-40 years) subjects; blood and urine samples were collected for 48 h post-dose. Non-compartmental analysis (NCA) of each tramadol and ODM enantiomer included area under the concentration-time curve (AUC), terminal elimination rate (k el), total body clearance, volume of distribution (V area/ F), and renal clearance (Clr0-48). A one-compartment population model of total tramadol concentration was parameterized with clearance (CL/F), volume of distribution (V/F), and mixed order absorption (first-order and zero-order absorption rate constants with lag times). RESULTS: NCA demonstrated comparable maximum plasma concentration (C max) and AUC between age groups for tramadol enantiomers, but significant differences in V area/ F (mean 34% higher) and k el (mean 28% lower) in the elderly. PK of ODM were significantly different in the elderly for AUC0-inf (mean 35% higher), Clr0-48 (mean 29% lower), and k el (mean 33% lower). The population analysis identified age as a covariate of V/F (young 305 L; elderly 426 L), with a 50% longer mean elimination half-life in the elderly. No differences in absorption processes were observed. CONCLUSIONS: Tramadol exposure was similar between the age groups; exposure to ODM was higher in elderly subjects.

Population pharmacokinetics of ceftolozane/tazobactam in healthy volunteers, subjects with varying degrees of renal function and patients with bacterial infections.

Ceftolozane/tazobactam is a novel antipseudomonal cephalosporin and ß-lactamase inhibitor in clinical development for treatment of complicated urinary tract (cUTI) and intra-abdominal (cIAI) infections and nosocomial pneumonia. The population pharmacokinetics of ceftolozane/tazobactam were characterized in healthy volunteers, subjects with varying degrees of renal function, and patients with cIAI or cUTI. Serum concentration data from 376 adults who received ceftolozane/tazobactam in doses ranging from 500 to 3000 mg were analyzed to identify factors contributing to the pharmacokinetic variability. Ceftolozane/tazobactam pharmacokinetics were well described by a linear two-compartment model with first-order elimination and moderate between-subject variability in both clearance and volume of distribution (Vc). For both ceftolozane and tazobactam, clearance was highly correlated with renal function with creatinine clearance influencing exposure, and infection influencing Vc. Body weight was an additional covariate affecting the Vc of ceftolozane. Other covariates tested, such as age, body weight, sex, ethnicity, and presence of infection, had no clinically relevant effects on exposure. The final pharmacokinetic models adequately described the plasma concentrations of ceftolozane and tazobactam and form the basis for further modeling and simulation including evaluation of probability of target attainment in a diverse population with varying demographics, degrees of renal function, and infection status.

Population pharmacokinetic modeling of motesanib and its active metabolite, M4, in cancer patients.

Motesanib is a small molecule and potent multikinase inhibitor with antiangiogenic and antitumor activity. Population pharmacokinetic (POPPK) modeling of motesanib and M4, an active metabolite, was performed to assess sources of variability in cancer patients. The analysis included data collected from 451 patients from 8 clinical trials with oral doses of motesanib ranging from 25 to 175 mg, either once daily or twice daily. The POPPK analyses were performed using nonlinear mixed-effect models with a sequential approach. Covariate effects of demographics and other baseline characteristics were assessed with stepwise covariate modeling. A 2-compartment model with food effect on absorption parameters fitted the PK data of motesanib well. The effects albumin and sex on apparent clearance (CL/F) of motesanib were statistically significant. The albumin effect was more important but remained below a 25% difference. A 1-compartment model fitted PK data of M4 well. Effects of race (Asian vs non-Asian) and dosing frequency were identified as statistically significant covariates on the CL/F of M4. The maximum effect of albumin would result in less than 25% change in motesanib CL/F and as such would not warrant any dosing adjustment. However, faster elimination of M4 in Asian patients requires further investigation.

Population pharmacokinetic analysis of thrombomodulin alfa to support dosing rationale in patients with renal impairment.

Thrombomodulin alfa is a soluble recombinant human thrombomodulin that was reported to enhance the reversal of disseminated intravascular coagulation (DIC) in subjects with sepsis or hematologic malignancy and reduce mortality in subjects with sepsis and DIC. Population pharmacokinetic (PK) analysis of thrombomodulin alfa was performed based on rich samples collected in 24 healthy subjects (0.02 and 0.06 mg/kg) and sparse samples collected in 368 subjects with sepsis and DIC (0.06 mg/kg). Sources of variability (baseline characteristics, markers of renal/liver function, hematocrit, and disease severity) were explored using non-linear mixed effect modeling to support dosing rationale in patients with sepsis and DIC. Plasma concentrations of thrombomodulin alfa were best fitted with a one-compartment model. Body weight and creatinine clearance were important covariates describing the PK of thrombomodulin alfa. Typical CL values in patients with normal renal function, or mild, moderate and severe renal impairment were 0.158, 0.145, 0.128, and 0.105 L/h, respectively. Based on simulations, a 0.06 mg/kg dosing of thrombomodulin alfa is expected to result in drug exposure within the therapeutic range of the product (300-5,400 ng/mL), with minimum risks of bleeding in patient with normal and impaired renal functions.

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.

Population pharmacokinetic analysis of dutogliptin, a selective dipeptidyl peptidase-4 inhibitor.

Dutogliptin is a selective dipeptidyl peptidase-4 inhibitor shown to be efficacious and safe in patients with type 2 diabetes mellitus (T2DM). Population pharmacokinetic (PK) analysis of dutogliptin was performed based on data collected in 561 healthy subjects and patients with T2DM enrolled in Phase I and II studies to assess sources of variability and support dosing rationale. The effect of extrinsic (formulations, fed/fasting conditions, potential drug-drug interaction with metformin) and intrinsic (baseline characteristics, markers of renal function, renal impairment category, and disease status) covariates was evaluated using non-linear mixed effect modeling. Plasma concentrations of dutogliptin were best fitted with a two-compartment model with a first-order rate constant of absorption (Ka) and a lag time. No differences were observed between healthy subjects and patients with T2DM. Apparent clearance (CL/F) and terminal elimination half-life of dutogliptin were 176 L/h and 12.2 hours, respectively. Typical CL/F values in patients with mild and moderate renal impairment were 121 and 79 L/h, respectively. No drug-drug interaction was observed with metformin. These results suggest that a reduction in dosing from 400 to 200 mg daily is warranted in T2DM patients with moderate renal impairment. No dose adjustments were deemed necessary for other evaluated patient characteristics and coadministration with metformin.

Differential Pharmacokinetics of Ganitumab in Patients With Metastatic Pancreatic Cancer Versus Other Advanced Solid Cancers.

Ganitumab is an investigational, fully human monoclonal antibody antagonist of the insulin-like growth factor-1 receptor (IGF1R) that has shown trends towards improved progression-free survival and overall survival in a phase 2 pancreatic cancer clinical trial. To characterize ganitumab pharmacokinetics (PK) and identify factors affecting PK, ganitumab serum concentration data from three clinical trials were analyzed. The PK of ganitumab as monotherapy and in combination with gemcitabine in patients with pancreatic or non-pancreatic cancer were assessed with a non-linear mixed-effect model. We found that ganitumab exhibited linear and time-invariant kinetics. A two-compartment model adequately described data over a dose range of 1-20 mg/kg with good predictive capability. Typical clearance and central volume of distribution values were 1.7- and 1.3-fold higher, respectively, in patients with pancreatic cancer than in patients with other advanced solid cancers, resulting in lower ganitumab exposure. Covariate analysis was used to evaluate effects of cancer type, gemcitabine coadministration, clinical study, demographics, and laboratory values on ganitumab PK. Pancreatic cancer type was the most significant covariate on clearance along with weight, albumin, and serum creatinine. Gemcitabine coadministration did not affect ganitumab clearance. Thus, disease state can significantly affect PK and should be considered when selecting the clinically effective dose.

Pharmacokinetic and pharmacodynamic modeling to determine the dose of ST-246 to protect against smallpox in humans.

Although smallpox has been eradicated, the United States government considers it a "material threat" and has funded the discovery and development of potential therapeutic compounds. As reported here, the human efficacious dose for one of these compounds, ST-246, was determined using efficacy studies in nonhuman primates (NHPs), together with pharmacokinetic and pharmacodynamic analysis that predicted the appropriate dose and exposure levels to provide therapeutic benefit in humans. The efficacy analysis combined the data from studies conducted at three separate facilities that evaluated treatment following infection with a closely related virus, monkeypox virus (MPXV), in a total of 96 NHPs. The effect of infection on ST-246 pharmacokinetics in NHPs was applied to humans using population pharmacokinetic models. Exposure at the selected human dose of 600 mg is more than 4-fold higher than the lowest efficacious dose in NHPs and is predicted to provide protection to more than 95% of the population.

Population pharmacokinetics of teduglutide following repeated subcutaneous administrations in healthy participants and in patients with short bowel syndrome and Crohn's disease.

Teduglutide is a GLP-2 analog currently evaluated for the treatment of short bowel syndrome, Crohn's disease, and other gastrointestinal disorders. The population pharmacokinetics (PK) of teduglutide were assessed following daily subcutaneous (SC) administrations of 2.5 to 80 mg doses in a total of 256 patients. A 1-compartment model with a site-specific rate constant of absorption in the abdomen, arm, and thigh was used to assess the PK of teduglutide. Apparent clearance (CL/F) of teduglutide in male participants was approximately 18% higher than that observed in female participants (12.4 vs 10.5 L/h, respectively). Body weight was detected as a significant covariate explaining the volume of distribution of teduglutide. The elimination half-life (t((1/2))) of teduglutide was also influenced by the body weight of participants. For a male patient weighing 50 and 90 kg, t((1/2)) of teduglutide was 0.897 and 2.99 hours, respectively. Renal and hepatic function of patients did not affect the PK of teduglutide. As a result, no dose adjustment was deemed necessary in patients with altered renal or liver function. The population PK model will help to support adequate drug labeling following SC administrations in patients and determine whether an individualized dosage is required.

Pharmacokinetic analysis of capsaicin after topical administration of a high-concentration capsaicin patch to patients with peripheral neuropathic pain.

Capsaicin, a pungent compound in chili peppers, is a highly selective agonist for the transient receptor potential vanilloid 1 receptor expressed in nociceptive sensory nerves. A high-concentration (640 microg/cm2) capsaicin patch, designated NGX-4010, is in clinical evaluation for the management of peripheral neuropathic pain. To determine systemic capsaicin exposure after single 60- or 90-minute NGX-4010 applications, plasma samples were collected from 173 patients with postherpetic neuralgia (PHN), painful human immunodeficiency virus-associated neuropathy (HIV-AN), and painful diabetic neuropathy (PDN). The percentages of patients with quantifiable levels of capsaicin at any time point were 31% for PHN (30 of 96), 7% for HIV-AN (3 of 44), and 3% for PDN (1 of 33). The maximum plasma concentration observed in any patient was 17.8 ng/mL. Due to the limited number of quantifiable levels, a population analysis was performed to characterize the pharmacokinetics (PK) of capsaicin. Plasma concentrations were fitted adequately using a 1-compartment model with first-order absorption and linear elimination. Capsaicin levels declined very rapidly, with a mean population elimination half-life of 1.64 hours. Mean area under the curve and C max values after a 60-minute application were 7.42 ng x h/mL and 1.86 ng/mL, respectively. Only a few correlations between calculated PK parameters and patient characteristics were observed. Duration and area of application of the patch were detected as significant covariates explaining the PK of capsaicin. Ninety-minute applications of NGX-4010 resulted in capsaicin area under the curve and Cmax values approximately 1.78- and 2.15-fold higher than those observed in patients treated for 60 minutes. Treatment on the feet (patients with HIV-AN and PDN) produced far lower systemic exposure than treatment on the trunk (patients with PHN). Finally, larger treatment areas were associated with statistically higher Vc/F values. The low systemic exposure and very rapid elimination half-life of capsaicin after NGX-4010 administration are unlikely to result in systemic effects and support the overall safety profile of this investigational cutaneous patch.

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.

Pharmacokinetics, safety, and tolerability of teduglutide, a glucagon-like peptide-2 (GLP-2) analog, following multiple ascending subcutaneous administrations in healthy subjects.

Teduglutide, a glucagon-like peptide-2 (GLP-2) analog, is currently being evaluated for the treatment of short-bowel syndrome, Crohn's disease, and other gastrointestinal disorders. The pharmacokinetics, safety, and tolerability of teduglutide in healthy subjects (N = 64) were assessed following daily subcutaneous administrations for 8 days in a double-blinded, randomized, placebo-controlled, ascending-dose study. Teduglutide treatments were administered as a 50-mg/mL (10, 15, 20, 25, 30, 50, and 80 mg) or 20-mg/mL (20 mg) formulation. Blood samples were collected on days 1 and 8, and plasma concentrations of teduglutide were measured using a liquid chromatography/tandem mass spectrometry method. Mean systemic exposures to teduglutide were very similar on days 1 and 8, suggesting minimal, if any, accumulation following once-daily repeated administrations. The apparent clearance of teduglutide following administration of the 50-mg/mL formulation was constant over the dose range, with mean values in male and female subjects of 0.155 and 0.159 L/h/kg, respectively. Peak plasma concentrations and total exposure of teduglutide after subcutaneous injection of a 20-mg/mL formulation (1.0 mL) were approximately 15% and 78% higher than those observed with the 50-mg/mL formulation (0.4 mL), respectively. Teduglutide treatments were safe and well tolerated. All but 1 adverse event was assessed as mild or moderate in severity. No relationship between teduglutide treatments and frequency of adverse events was observed, with the exception of injection site pain, which increased as a function of dose and injected volume. Results from the current study will assist in the dose selection in future efficacy studies.

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.