Developmental pharmacokinetics of ciclosporin--a population pharmacokinetic study in paediatric renal transplant candidates

What is already known about this subject

• Ciclosporin is an immunosuppressant drug with a narrow therapeutic index and large variability in pharmacokinetics.
• It is likely that the inter- and intraindividual variability in ciclosporin pharmacokinetics and dose requirements is even larger in children than in adults as a result of variation in biological maturation status.
• However, data on the developmental pharmacokinetics of ciclosporin, as well as other CYP3A4 substrate drugs, in children are scarce.

What this study adds

• Adult CYP3A4 activity seems to be reached by the age of 6–12 months, and allometrically scaled body weight is a good predictor of the hepatic clearance of ciclosporin, a CYP3A4 substrate.
• Ciclosporin oral bioavailability, known previously to display large interindividual variability, is not influenced by age.
• These conclusions were reached using a robust modelling approach (NONMEM) with rich paediatric pharmacokinetic data collected after full i.v. and p.o. profiles.

Aims

To use population pharmacokinetic modelling to characterize the influence of developmental and demographic factors on the pharmacokinetic variability of ciclosporin.

Methods

Pharmacokinetic modelling was performed in NONMEM using a dataset comprising 162 pretransplant children, aged 0.36–17.5 years. Ciclosporin was given intravenously (3 mg kg⁻¹) and orally (10 mg kg⁻¹) on separate occasions followed by blood sampling for 24 h.

Results

A three-compartment model with first-order absorption without lag-time best described the pharmacokinetics of ciclosporin. The most important covariate affecting systemic clearance (CL) and distribution volume (V) was body weight (BW; scaled allometrically), responsible for a fourfold difference in uncorrected ciclosporin CL and a sixfold difference in ciclosporin V. The other significant covariates, haematocrit, plasma cholesterol and creatinine, were estimated to explain 20–30% of interindividual differences in CL and V of ciclosporin. No age-related changes in oral bioavailability or in BW-normalized V were seen. The BW-normalized CL (CL/BW) declined with age and prepubertal children (<8 years) had an approximately 25% higher CL/BW than did older children. Normalization of CL for allometric BW (BW^3/4) removed its relationship to age.

Conclusion

The relationship between CL and allometric BW is consistent with a gradual reduction in relative liver size, until adult values, and a relatively constant CYP3A4 content in the liver from about 6–12 months of age to adulthood. Ciclosporin oral bioavailability, known previously to display large interindividual variability, is not influenced by age. These findings can enable better individualization of ciclosporin dosing in infants, children and adolescents.     

Population pharmacokinetics modeling of levetiracetam in Chinese children with epilepsy

Aim:

To establish a population pharmacokinetics (PPK) model of levetiracetam in Chinese children with epilepsy.

Methods:

A total of 418 samples from 361 epileptic children in Peking University First Hospital were analyzed. These patients were divided into two groups: the PPK model group (n=311) and the PPK validation group (n=50). Levetiracetam concentrations were determined by HPLC. The PPK model of levetiracetam was established using NONMEM, according to a one-compartment model with first-order absorption and elimination. To validate the model, the mean prediction error (MPE), mean squared prediction error (MSPE), root mean-squared prediction error (RMSPE), weight residues (WRES), and the 95% confidence intervals (95% CI) were calculated.

Results:

A regression equation of the basic model of levetiracetam was obtained, with clearance (CL/F)=0.988 L/h, volume of distribution (V/F)=12.3 L, and K_a=1.95 h⁻¹. The final model was as follows: K_a=1.56 h⁻¹, V/F=12.1 (L), CL/F=1.04×(WEIG/25)^0.583 (L/h). For the basic model, the MPE, MSPE, RMSPE, WRES, and the 95%CI were 9.834 (−0.587–197.720), 50.919 (0.012–1286.429), 1.680 (0.021–34.184), and 0.0621 (−1.100–1.980). For the final model, the MPE, MSPE, RMSPE, WRES, and the 95% CI were 0.199 (−0.369–0.563), 0.002082 (0.00001–0.01054), 0.0293 (0.001−0.110), and 0.153 (−0.030–1.950).

Conclusion:

A one-compartment model with first-order absorption adequately described the levetiracetam concentrations. Body weight was identified as a significant covariate for levetiracetam clearance in this study. This model will be valuable to facilitate individualized dosage regimens.     

Population pharmacokinetics of oral diclofenac for acute pain in children

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Diclofenac is an effective oral analgesic for acute postoperative pain. In adults 25 mg is half as effective as 50 mg, but 50 mg and 100 mg are similarly effective (ceiling effect). Diclofenac has linear pharmacokinetics in this range.
• Diclofenac is frequently used ‘off-label’ in children for acute pain but optimum dosing is unclear (dosing of diclofenac in clinical paediatric studies ranges from 0.5–2.5 mg kg⁻¹). There is currently no licensed oral paediatric formulation of diclofenac.

WHAT THIS STUDY ADDS

• Using a new diclofenac oral suspension, a dose of 1 mg kg⁻¹ in children aged 1 to 12 years gives a similar exposure to 50 mg in adults; paediatric patients are unlikely to benefit from higher doses.

AIMS

To develop a population pharmacokinetic model for a new diclofenac suspension (50 mg 5 ml⁻¹) in adult volunteers and paediatric patients, and recommend a dose for acute pain in children.

METHODS

Blood samples were drawn at the start and end of surgery, and on removal of the venous cannula from 70 children (aged 1 to 12 years, weight 9 to 37 kg) who received a preoperative oral 1 mg kg⁻¹ dose; these were pooled with rich (14 post-dose samples) data from 30 adult volunteers. Population pharmacokinetic modelling was undertaken with NONMEM. The optimum adult dose of diclofenac for acute pain is 50 mg. Simulation from the final model was performed to predict a paediatric dose to achieve a similar AUC to 50 mg in adults.

RESULTS

A total of 558 serum diclofenac concentrations from 100 subjects was used in the pooled analysis. A single disposition compartment model with first order elimination and dual absorption compartments was used. The estimates of CL/F and V_D/F were 53.98 l h⁻¹ 70 kg⁻¹ and 4.84 l 70 kg⁻¹ respectively. Allometric size models appeared to predict adequately changes in CL and V_D with age. Of the simulated doses investigated, 1 mg kg⁻¹ gave paediatric AUC_{(0, 12 h)} to adult 50 mg AUC_{(0, 12 h)} ratios of 1.00, 1.08 and 1.18 for ages 1–3, 4–6 and 7–12 years respectively.

CONCLUSIONS

This study has shown 1 mg kg⁻¹ diclofenac to produce similar exposure in children aged 1 to 12 years as 50 mg in adults, and is acceptable for clinical practice; patients are unlikely to obtain further benefit from higher doses.     

Population pharmacokinetics of levamisole in children with steroid-sensitive nephrotic syndrome

Aim

The aim was to investigate the population pharmacokinetics of levamisole in children with steroid-sensitive nephrotic syndrome.

Methods

Non-linear mixed effects modelling was performed on samples collected during a randomized controlled trial. Samples were collected from children who were receiving 2.5 mg kg^–1 levamisole (or placebo) orally once every other day. One hundred and thirty-six plasma samples were collected from 38 children from India and Europe and included in the analysis. A one compartment model described the data well.

Results

The apparent clearance rate (CL/F) and distribution volume (V/F) were 44 l h^–1 70 kg^–1 and 236 l 70 kg^–1, respectively; estimated interindividual variability was 32–42%. In addition to allometric scaling of CL/F and V/F to body weight, we identified a significant proportional effect of age on CL/F (–10.1% per year). The pharmacokinetics parameters were not affected by gender, tablet strength or study centre. The median (interquartile range) maximum plasma concentration of levamisole was 438.3 (316.5–621.8) ng ml^–1, and the median area under the concentration–time curve was 2847 (2267–3761) ng ml^–1 h. Median t_max and t_½ values were 1.65 (1.32–2.0) h and 2.60 (2.06–3.65) h, respectively.

Conclusions

Here, we present the first pharmacokinetic data regarding levamisole in children with steroid-sensitive nephrotic syndrome. The pharmacokinetic profile of levamisole in children was similar to findings reported in adults, although the elimination rate was slightly higher in children.     

Population pharmacokinetics of sirolimus in de novo Chinese adult renal transplant patients

AIMS

This study was aimed at determining the population pharmacokinetics of sirolimus and identifying factors that explain pharmacokinetic variability in de novo Chinese adult renal transplant patients.

METHODS

Data were retrospectively extracted from a formal multicentre clinical trial, which was originally designed to evaluate the safety and efficacy of ciclosporin dose reduction and ciclosporin elimination in patients receiving sirolimus. All patients received 12-month treatment, i.e. induction therapy with ciclosporin, sirolimus and corticosteroids during the first 3 months followed by either ciclosporin dose reduction or ciclosporin discontinuation thereafter. Eight-hundred and four sirolimus trough blood concentrations (C₀) from 112 patients were used to develop a population pharmacokinetic model using the nonmem program. A one-compartment model with first-order absorption and elimination was selected as the base model. The influence of demographic characteristics, biochemical and haematological indices, ciclosporin daily dose, ciclosporin C₀ as well as other commonly used co-medications were explored.

RESULTS

The typical values with interindividual variability for apparent clearance (CL/F) and apparent volume of distribution (V/F) were 10.1 l h⁻¹ (23.8%) and 3670 l (56.7%), respectively. The residual variability was 29.9%. CL/F decreased significantly with silymarin or glycyrrhizin co-therapy in hepatically impaired patients, and with increasing total cholesterol levels or ciclosporin C₀. Moreover, CL/F increased nonlinearly with increasing sirolimus daily dose. The median parameter estimates from a nonparametric bootstrap procedure were comparable and within 5% of the estimates from nonmem.

CONCLUSIONS

These results provide important information for clinicians to optimize sirolimus regimens in Chinese renal transplant patients.     

Covariate effects and population pharmacokinetics of lamivudine in HIV-infected children

Aim

Lamivudine is used as first line therapy in HIV-infected children. Yet, like many other paediatric drugs, its dose rationale has been based on limited clinical data, without thorough understanding of the effects of growth on drug disposition. Here we use lamivudine to show how a comprehensive population pharmacokinetic model can account for the influence of demographic covariates on exposure (i.e. AUC and C_max).

Methods

Data from three paediatric trials were used to describe the pharmacokinetics across the overall population. Modelling was based on a non-linear mixed effects approach. A stepwise procedure was used for covariate model building.

Results

A one compartment model with first order elimination best described the pharmacokinetics of lamivudine in children. The effect of weight on clearance (CL) and volume of distribution (V) was characterized by an exponential function, with exponents of 0.705 and 0.635, respectively. For a child with median body weight (17.6 kg), CL and V were 16.5 (95% CI 15.2, 17.7) l h⁻¹ and 46.0 (95% CI 42.4, 49.5) l, respectively. There were no differences between formulations (tablet and solution). The predicted AUC(0,12 h) after twice daily doses of 4 mg kg⁻¹ ranged from 4.44 mg l⁻¹ h for children <14 kg to 7.25 mg l⁻¹ h for children >30 kg.

Conclusions

The use of meta-analysis is critical to identify the correct covariate-parameter relationships, which must be assessed before a model is applied for predictive purposes (e.g. defining dosing recommendations for children). In contrast to prior modelling efforts, we show that the covariate distribution in the target population must be considered.     

Translational pharmacokinetic–pharmacodynamic modelling; application to cardiovascular safety data for PF-00821385, a novel HIV agent

AIM

To assess the translation of pharmacokinetic–pharmacodynamic (PK–PD) relationships for heart rate effects of PF-00821385 in dog and man.

METHODS

Cardiovascular telemetric parameters and concentration data were available for animals receiving active doses (0.5–120 mg kg⁻¹, n= 4) or vehicle. PF-00821385 was administered to 24 volunteers and pharmacokinetic and vital signs data were collected. PK–PD models were fitted using nonlinear mixed effects.

RESULTS

Compartmental models with linear absorption and clearance were used to describe pharmacokinetic disposition in animal and man. Diurnal variation in heart and pulse rate was best described with a single cosine function in both dog and man. Canine and human heart rate change were described by a linear model with free drug slope 1.76 bpm µM⁻¹[95% confidence interval (CI) 1.17, 2.35] in the dog and 0.76 bpm µM⁻¹ (95% CI 0.54, 1.14) in man.

CONCLUSIONS

The preclinical translational of concentration–response has been described and the potential for further interspecies extrapolation and optimization of clinical trial design is addressed.     

Population pharmacokinetics and haemodynamic effects of norepinephrine in hypotensive critically ill children

Aim

The aim of the study was to investigate the pharmacokinetics and pharmacodynamics of norepinephrine in hypotensive critically ill children, including associated variability factors.

Methods

This was a prospective study in an 18-bed neonatal and paediatric intensive care unit. All children were aged less than 18 years, weighed more than 1500 g and required norepinephrine for systemic arterial hypotension. The pharmacokinetics and haemodynamic effects were described using the non-linear mixed effect modelling software MONOLIX.

Results

Norepinephrine dosing infusions ranging from 0.05 to 2 μg kg⁻¹ min⁻¹ were administered to 38 children whose weight ranged from 2 to 85 kg. A one compartment open model with linear elimination adequately described the norepinephrine concentration–time courses. Bodyweight (BW) was the main covariate influencing norepinephrine clearance (CL) and endogenous norepinephrine production rate (q0) via an allometric relationship: CL(BWi) = θ_CL × (BWi)^3/4 and q0(BWi) = θ_q0 × (BWi)^3/4. The increase in mean arterial pressure (MAP) as a function of norepinephrine concentration was well described using an E_max model. The effects of post-conceptional age (PCA) and number of organ dysfunctions were significant on basal MAP level (MAP_0i = MAP₀ × PCA/9_i^0.166) and on the maximal increase in MAP (32 mmHg and 12 mmHg for a number of organ dysfunctions ≤3 and ≥4, respectively).

Conclusion

The pharmacokinetics and haemodynamic effects of norepinephrine in hypotensive critically ill children highlight the between-subject variability which is related to the substantial role of age, BW and severity of illness. Taking into account these individual characteristics may help clinicians in determining an appropriate initial a priori dosing regimen.     

Population pharmacokinetics of abacavir in infants,toddlers and children

Aims

To characterize the pharmacokinetics of abacavir in infants, toddlers and children and to assess the influence of covariates on drug disposition across these populations.

Methods

Abacavir concentration data from three clinical studies in human immunodeficiency virus-infected children (n = 69) were used for model building. The children received either a weight-normalized dose of 16 mg kg⁻¹ day⁻¹ or the World Health Organization recommended dose based on weight bands. A population pharmacokinetic analysis was performed using nonlinear mixed effects modelling VI. The influence of age, gender, bodyweight and formulation was evaluated. The final model was selected according to graphical and statistical criteria.

Results

A two-compartmental model with first-order absorption and first-order elimination best described the pharmacokinetics of abacavir. Bodyweight was identified as significant covariate influencing the apparent oral clearance and volume of distribution. Predicted steady-state maximal plasma concentration and area under the concentration–time curve from 0 to 12 h of the standard twice daily regimen were 2.5 mg l⁻¹ and 6.1 mg h l⁻¹ for toddlers and infants, and 3.6 mg l⁻¹ and 8.7 mg h l⁻¹ for children, respectively. Model-based predictions showed that equivalent systemic exposure was achieved after once and twice daily dosing regimens. There were no pharmacokinetic differences between the two formulations (tablet and solution). The model demonstrated good predictive performance for dosing prediction in individual patients and, as such, can be used to support therapeutic drug monitoring in conjunction with sparse sampling.

Conclusions

The disposition of abacavir in children appears to be affected only by differences in size, irrespective of the patient''s age. Maturation processes of abacavir metabolism in younger infants should be evaluated in further studies to demonstrate the potential impact of ontogeny.     

Population pharmacokinetics and optimal design of paediatric studies for famciclovir

AIMS

To develop a population pharmacokinetic model for penciclovir (famciclovir is a prodrug of penciclovir) in adults and children and suggest an appropriate dose for children. Furthermore, to develop a limited sampling design based on sampling windows for three different paediatric age groups (1–2, 2–5 and 5–12 years) using an adequate number of subjects for future pharmacokinetic studies.

METHODS

Penciclovir plasma data from six different adult and paediatric studies were supplied by Novartis. Population pharmacokinetic modelling was undertaken in NONMEM version VI. Simulations in MATLAB were used to select an oral paediatric dose that gives similar exposure to 500 mg in adults. Optimal sampling times and sampling windows were obtained in MATLAB and simulations in NONMEM were used to select adequate sample sizes for three paediatric age groups.

RESULTS

A two-compartment, first-order absorption model with an absorption lag time, allometric weight models on V₁, V₂ and Q, and an allometric weight model, age and creatinine clearance as covariates on CL adequately describe the pharmacokinetics of penciclovir in adults and children. Estimated CL (l h⁻¹ 70 kg⁻¹) and V_ss (l.70 kg⁻¹) were 31.2 and 83.1, respectively. An oral dose of 10 mg kg⁻¹ body weight in children was predicted to give similar exposure as 500 mg in adults. A single sampling windows design (0.25–0.4, 0.5–1, 1.25–1.75, 2.75–3.5 and 7.25–8 h) for five samples per subject and 10 subjects in each of the paediatric age groups is recommended for future studies.

CONCLUSIONS

A population pharmacokinetic model of penciclovir in adults and children has been developed. A prospective study design, including dose adjustment, cohort size and blood sampling design has been recommended.     

The effects and safety of dexibuprofen compared with ibuprofen in febrile children caused by upper respiratory tract infection

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• The analgesic and anti-inflammatory efficacy of dexibuprofen compared with ibuprofen in adults with osteoarthritis, rheumatoid arthritis and dental pain.

WHAT THIS STUDY ADDS

• Dexibuprofen is as effective and tolerable as ibuprofen, and a dose of 5 mg kg⁻¹ of dexibuprofen would be sufficient to control fever caused by upper respiratory tract infection in children.

AIM

To evaluate the antipyretic efficacy and tolerability of dexibuprofen compared with ibuprofen in children with fever caused by upper respiratory tract infection (URTI).

METHODS

The study population consisted of children aged 6 months to 14 years. At the time of visit to the hospital, the children had fever; the cause of fever was determined to be URTI by a paediatrician based on history taking and physical examination. The study was a multicentre, randomized, double-blind, controlled parallel group, comparative, Phase 3 clinical trial, conducted at three hospitals. By using a computer-based random assignment program, the subjects were allocated to the following three groups: 5 mg kg⁻¹ dexibuprofen group, 7 mg kg⁻¹ dexibuprofen group, and 10 mg kg⁻¹ ibuprofen group.

RESULTS

In the clinical trial of the antipyretic action of dexibuprofen in patients with fever caused by URTI, there was no statistically significant difference in maximal decrease of temperature and mean time to become apyrexial among the 5 mg kg⁻¹ dexibuprofen, 7 mg kg⁻¹ dexibuprofen and 10 mg kg⁻¹ ibuprofen groups (P > 0.05). There also was no significant difference in adverse drug reaction (P > 0.05).

CONCLUSIONS

Dexibuprofen is as effective and tolerable as ibuprofen. A dose of 5 mg kg⁻¹ and 7 mg kg⁻¹ dexibuprofen in place of 10 mg kg⁻¹ ibuprofen would be sufficient to control fever caused by URTI in children.     

Preclinical pharmacokinetics of TPN729MA,a novel PDE5 inhibitor,and prediction of its human pharmacokinetics using a PBPK model

Aim:

TPN729MA is a novel selective PDE5 inhibitor currently under clinical development in China for the treatment of erectile dysfunction. In this study we characterized its preclinical pharmacokinetics (PK) and predict its human PK using a physiologically based pharmacokinetic (PBPK) model.

Methods:

The preclinical PK of TPN729MA was studied in rats and dogs. Human clearance (CL) values for TPN729MA were predicted from various allometric methods and from intrinsic CL determined in human liver microsomes. Human PK and plasma concentration versus time profiles of TPN729MA were predicted by using a PBPK model in GastroPlus. Considering the uncertainties in the prediction, a preliminary human study was conducted in 3 healthy male volunteers with an oral dose of 25 mg.

Results:

After a single intravenous administration of TPN729MA at a dose of 1 mg/kg in rats and 3 mg/kg in dogs, the plasma CL was 69.7 mL·min⁻¹·kg⁻¹ in rats and 26.3 mL·min⁻¹·kg⁻¹ in dogs, and the steady-state volumes of distribution (V_ss) were 7.35 L/kg in rats and 6.48 L/kg in dogs. The oral bioavailability of TPN729MA was 10% in rats and above 34% in dogs. Profiles of predicted plasma concentration versus time were similar to those observed in humans at 25 mg, and the predicted T_max, C_max and AUC values were within 2-fold of the observed values.

Conclusion:

TPN729MA demonstrates good preclinical PK. This compound is a valuable candidate for further clinical development. This study shows the benefits of using a PBPK model to predict PK in humans.     

Pharmacokinetic and pharmacodynamic analysis of enteric-coated mycophenolate sodium: limited sampling strategies and clinical outcome in renal transplant patients

AIMS

Pharmacokinetic (PK) and pharmacodynamic (PD) monitoring strategies and clinical outcome were evaluated in enteric-coated mycophenolate sodium (EC-MPS)-treated renal allograft recipients.

METHODS

PK [mycophenolic acid (MPA)] and PD [inosine monophosphate dehydrogenase (IMPDH) activity] data were analysed in 66 EC-MPS and ciclosporin A (CsA)-treated renal allograft recipients. Adverse events were considered in a follow-up period of 12 weeks.

RESULTS

Analyses confirmed a limited sampling strategy (LSS) consisting of PK and PD data at predose, 1, 2, 3 and 4 h after oral intake as an appropriate sampling method (MPA r²= 0.812; IMPDH r²= 0.833). MPA AUC_0–12 of patients with early biopsy-proven acute rejection was significantly lower compared with patients without a rejection (median MPA AUC_0–12 28 µg*h ml⁻¹ (7–45) vs. 40 µg*h ml⁻¹ (16–130), P < 0.01), MPA AUC_0–12 of patients with recurrent infections was significantly higher compared with patients without infections (median MPA AUC_0–12 65 µg*h ml⁻¹ (range 37–130) vs. 37 µg*h ml⁻¹ (range 7–120), P < 0.005). Low 12-h IMPDH enzyme activity curve (AEC_0–12) was associated with an increased frequency of gastrointestinal side-effects (median IMPDH AEC_0–12 43 nmol*h mg⁻¹ protein h⁻¹[range 12–67) vs. 75 nmol*h mg⁻¹ protein h⁻¹ (range 15–371), P < 0.01].

CONCLUSIONS

Despite highly variable absorption data, an appropriate LSS might be estimated by MPA AUC_0–4 and IMPDH AEC_0–4 in renal transplant patients treated with EC-MPS and CsA. Regarding adverse events, the suggested MPA-target AUC_0–12 from 30 to 60 µg*h ml⁻¹ seems to be appropriate in renal allograft recipients.     

The pharmacokinetic profile of sitaxsentan, a selective endothelin receptor antagonist, in varying degrees of renal impairment

What is already known about this subject

• The initial indication for endothelin (ET) receptor antagonism as a treatment strategy, primary pulmonary hypertension, is now expanding to include scleroderma, which can cause both pulmonary and renal disease.
• It is important to understand the effects of impaired renal function on the pharmacokinetics of these drugs to allow appropriate dosing in individuals with impaired renal function.

What this study adds

• Sitaxsentan, an oral selective endothelin A receptor antagonist, is licensed for the treatment of pulmonary hypertension, and studies of this drug in CKD are planned.
• The pharmacokinetic profile of sitaxsentan is unchanged in subjects with varying degrees of renal impairment.
• The results of this study will allow confident dosing of sitaxsentan in individuals with renal impairment, and inform future studies.

Aim

To investigate the pharmacokinetic profile of a single 100-mg oral dose of sitaxsentan, a selective endothelin type A receptor antagonist, in subjects with normal and impaired renal function.

Methods

This was an open label, single oral dose study in subjects with normal [creatinine clearance (CrCL) ≥ 80 ml min⁻¹] and impaired renal function (mild renal impairment CrCL 51–80 ml min⁻¹, moderate impairment CrCL 31–50 ml min⁻¹, severe impairment CrCL ≤ 30 ml min⁻¹). All subjects received a dose of 100 mg sitaxsentan.

Results

Twenty-four subjects were enrolled, six in each of the normal and three renal impairment groups. The mean plasma sitaxsentan concentrations were comparable across the groups, as were the mean values for C_max (10.3–13.9 µg ml⁻¹), AUC_∞ (18.7–22.5 h µg⁻¹ ml⁻¹), oral clearance (CL/F, 82.3–94.9 ml min⁻¹), volume of distribution (Vz/F, 64.8–69.6 l) and elimination half-life (t_1/2, 8.6–9.6 h). There was substantial overlap among the four groups in the individual subject values for CL/F and Vz/F and no relationship between either of these parameters and CrCL.

Conclusion

After a single 100-mg oral dose of sitaxsentan there were no differences in its pharmacokinetics among subjects with normal or impaired renal function.     

Ciclosporin kinetics in children after stem cell transplantation

AIMS

To develop a limited sampling strategy to determine ciclosporin systemic exposure [area-under-the-curve(AUC)]. This is meant to be the first step in a future study of the relationship between AUC and the biological effects of ciclosporin.

METHODS

The pharmacokinetics of ciclosporin was investigated prospectively following stem cell transplantation (SCT) in 17 children, aged 1.8–16.1 years. Ciclosporin was given twice daily, intravenously over a short infusion of 2 h duration during the early post-SCT period, or orally later on, when oral medication was well tolerated. Parameter estimation was performed using nonlinear mixed effect modelling as implemented in the NONMEM program. Individual empirical Bayes estimates of clearance and distribution volume were correlated with the demographic variables.

RESULTS

Pharmacokinetics was described adequately with a two-compartment model with lag time (population estimates: CL = 11.3 l h⁻¹; V_c = 16.5 l; V_p = 59.9 l; t_1/2 absorption = 0.78 h, t_lag = 0.6 h). The AUCs, determined for the combination of trough level with one time point between 2 and 3 h after dosing, correlated very well with the reference AUC (r² = 0.97). No correlation was found between clearance and distribution volume, and the demographic patient variables length, body weight, age and glomerular filtration rate.

CONCLUSION

A two-point limited sampling strategy, in combination with a Bayesian fitting procedure using the pharmacokinetic population model described, can adequately determine the AUC of ciclosporin. Since no correlation between clearance and body weight was found, dosing ciclosporin per kg bodyweight is not supported by the results of this study. We suggest starting with a fixed dose, followed by AUC determination and dose adjustment.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Ciclosporin is an immunosuppressant drug that is commonly used as prophylaxis against graft-versus-host disease (GVHD) after allogeneic haematopoietic stem cell transplantation (SCT) in children.
• Therapeutic drug monitoring is necessary because of its unpredictable absorption and narrow therapeutic window.
• Data on the pharmacokinetics of ciclosporin and the relation between its systemic exposure, as reflected by the AUC (area-under-the-curve), and the biological effect as GVHD prophylaxis are scarce in children after SCT.

WHAT THIS STUDY ADDS

• An adequate estimate of the systemic exposure of ciclosporin, following limiting sampling after intravenous and oral administration, can be obtained in children after SCT by determining the AUC using a two-compartment pharmacokinetic model with lag time in combination with a limited sampling strategy.
• Large interindividual variability in ciclosporin clearance was found, which was independent of body weight; this finding justifies a dosing strategy distinct from that per kg body weight.
• Limited sampling modelling may serve as a tool to study the relationship between systemic exposure (∼AUC) and biological effects of ciclosporin, i.e. facilitation of engraftment, prevention of GVHD and avoidance of toxic effects of ciclosporin.

     

Population pharmacokinetics of lamotrigine in Chinese children with epilepsy

Aim:

To establish a population pharmacokinetics (PPK) model for lamotrigine (LTG) in Chinese children with epilepsy in order to formulate an individualized dosage guideline.

Methods:

LTG steady-state plasma concentration data from therapeutic drug monitoring (TDM) were collected retrospectively from 284 patients, with a total of 404 plasma drug concentrations. LTG concentrations were determined using a HPLC method. The patients were divided into 2 groups: PPK model group (n=116) and PPK valid group (n=168). A PPK model of LTG was established with NONMEM based on the data from PPK model group according to a one-compartment model with first order absorption and elimination. To validate the basic and final model, the plasma drug concentrations of the patients in PPK model group and PPK valid group were predicted by the two models.

Results:

The final regression model for LTG was as follows: CL (L/h)=1.01^*(TBW/27.87)^0.635*e^−0.753*VPA*e^0.868*CBZ*e^0.633*PB, Vd (L)= 16.7^*(TBW/27.87). The final PPK model was demonstrated to be stable and effective in the prediction of serum LTG concentrations by an internal and external approach validation.

Conclusion:

A PPK model of LTG in Chinese children with epilepsy was successfully established with NONMEM. LTG concentrations can be predicted accurately by this model. The model may be very useful for establishing initial LTG dosage guidelines.     

Effect of dronedarone on renal function in healthy subjects

What is already known about this subject

• Creatinine clearance (CL) is used to assess glomerular filtration rate (GFR). However, it is known to slightly overestimate the true GFR, due to renal tubular secretion of creatinine.
• During phase I-III clinical trials, a 10–15% increase in serum creatinine has been observed both in healthy subjects and patients receiving the new antiarrhythmic agent dronedarone.

What this study adds

• Dronedarone affects the renal handling of creatinine and N-methylnicotinamide, two cations, while leaving unchanged GFR, assessed through sinistrin CL, and renal plasma flow and anion secretion, assessed through para-amino-hippurate CL.
• This suggests a specific action of dronedarone on renal organic cation transport explaining the limited, reversible effect of dronedarone on serum creatinine, which must not be interpreted as reflecting an impairment of renal function, but which may indicate an interaction potential with cationic drugs.

Aims

To assess the effects of dronedarone on renal function and tubular cation handling.

Methods

Twelve healthy males were enrolled in a randomized, cross-over, placebo-controlled, double-blind study. They received 400 mg dronedarone or placebo twice daily for 7 days. Baseline and on-treatment renal function tests were performed under strict standardization of intakes, by assessing creatinine, sinistrin, para-amino-hippurate (PAH) and N-methylnicotinamide (NMN) CLs, and electrolyte excretion.

Results

Compared with placebo, dronedarone significantly decreased renal creatinine CL (mean 138–119 ml min⁻¹ after dronedarone vs. 142–149 ml min⁻¹ after placebo) and NMN CL (448–368 ml min⁻¹vs. 435–430 ml min⁻¹), but did not alter renal sinistrin CL, PAH CL and other renal parameters.

Conclusions

Dronedarone reduces renal creatinine and NMN clearance by about 18%, without evidence of an effect on GFR, renal plasma flow or electrolyte exchanges. This suggests a specific partial inhibition of tubular organic cation transporters (OCT). A limited increase in serum creatinine is therefore expected with dronedarone treatment, but does not mean there is a decline in renal function.     

Dried blood spots and sparse sampling: a practical approach to estimating pharmacokinetic parameters of caffeine in preterm infants

Aims

Dried blood spots (DBS) alongside micro‐analytical techniques are a potential solution to the challenges of performing pharmacokinetic (PK) studies in children. However, DBS methods have received little formal evaluation in clinical settings relevant to children. The aim of the present study was to determine a PK model for caffeine using a ‘DBS/microvolume platform’ in preterm infants.

Methods

DBS samples were collected prospectively from premature babies receiving caffeine for treatment of apnoea of prematurity. A non‐linear mixed effects approach was used to develop a population PK model from measured DBS caffeine concentrations. Caffeine PK parameter estimates based on DBS data were then compared with plasma estimates for agreement.

Results

Three hundred and thirty‐eight DBS cards for caffeine measurement were collected from 67 preterm infants (birth weight 0.6–2.11 kg). 88% of cards obtained were of acceptable quality and no child had more than 10 DBS samples or more than 0.5 ml of blood taken over the study period. There was good agreement between PK parameters estimated using caffeine concentrations from DBS samples (CL = 7.3 ml h⁻¹ kg⁻¹; V = 593 ml kg⁻¹; t_1/2 = 57 h) and historical caffeine PK parameter estimates based on plasma samples (CL = 4.9–7.9 ml h⁻¹ kg⁻¹; V = 640–970 ml kg⁻¹; t_1/2 = 101–144 h). We also found that changes in blood haematocrit may significantly confound estimates of caffeine PK parameters based on DBS data.

Conclusions

This study demonstrates that DBS methods can be applied to PK studies in a vulnerable population group and are a practical alternative to wet matrix sampling techniques.     

Modified renal function in pregnancy: impact on emtricitabine pharmacokinetics

Aims

The aims were to describe emtricitabine (FTC) pharmacokinetics in a large population of pregnant women during the different trimesters of pregnancy, and to explain FTC pharmacokinetic variability during pregnancy.

Methods

FTC plasma concentrations were measured in 103 non-pregnant and 83 pregnant women, including women in the different trimesters of pregnancy and on the day of delivery. A total of 457 plasma concentrations were available for analysis. A population pharmacokinetic model was developed with Monolix 4.1.3.

Results

FTC pharmacokinetics was best described by a two compartment model. The effect of creatinine clearance on apparent elimination clearance (CL/F) was significant. CL/F in pregnant women was significantly higher compared with non-pregnant women (geometric mean 24.1 vs 20.5 l h⁻¹, P < 0.001), reflecting a modified renal function. FTC daily exposures (AUC) during pregnancy were lower than AUC in non-pregnant women, regardless of the trimester of pregnancy. FTC AUC geometric means were 8.38 mg l⁻¹h in the second trimester of pregnancy, 8.16 mg l⁻¹h in the third trimester of pregnancy, 8.30 mg l⁻¹h on the day of delivery and 9.77 mg l⁻¹h in non-pregnant women. FTC concentrations 24 h after administration were lower in pregnant women compared with non-pregnant women (0.054 vs. 0.079 mg l⁻¹, P < 0.001) but still above the inhibitory concentration 50%.

Conclusions

FTC CL/F was increased by 18% during pregnancy, reflecting a modified renal function with 50% increase in estimated glomerular filtration rate. However, the impact of this modified renal function on FTC pharmacokinetics was not sufficiently large to consider dose adjustments during pregnancy.