Population pharmacokinetics of S-ketamine and norketamine in healthy volunteers after intravenous and oral dosing.

PURPOSE: Low-dose ketamine is a lucrative therapeutic approach in cancer pain, perioperative treatment of pain, and management of treatment-resistant depression. The analgesic potency of its main metabolite norketamine is thought to be one third that of ketamine. However, few studies exist on the pharmacokinetics of orally administered S-ketamine. METHODS: In our study, 11 healthy volunteers received S-ketamine 0.25 mg/kg orally and 0.125 mg/kg intravenously. S-ketamine and norketamine concentrations were measured up to 23.5 h post-dose. A population pharmacokinetic model was built to describe S-ketamine and norketamine pharmacokinetics. RESULTS: A three-compartment model for both S-ketamine and norketamine best described the data. To accommodate for the extensive formation of norketamine after oral S-ketamine, a separate presystemic absorption-phase component was included in addition to its systemic formation. The oral bioavailability of S-ketamine was low, 8% (11% interindividual variability), and its clearance was high, 95 L/h/70 kg (13% interindividual variability). Simulations suggested that after oral dosing, norketamine AUC at steady state is 16.5 times higher than that of S-ketamine. CONCLUSIONS: Given that the analgesic effect of S-ketamine is due to both S-ketamine and norketamine, relatively small oral doses of S-ketamine can be assumed to be a feasible alternative to repeated intravenous dosing, for example in the setting of chronic pain.

A time-to-event model for acute rejections in paediatric renal transplant recipients treated with ciclosporin A.

AIMS: Ciclosporin A (CsA) dosing in immunosuppression after paediatric kidney transplantation remains challenging, and appropriate target CsA exposures (AUCs) are controversial. This study aimed to develop a time-to-first-acute rejection (AR) model and to explore predictive factors for therapy outcome. METHODS: Patient records at the Children's Hospital in Helsinki, Finland, were analysed. A parametric survival model in NONMEM was used to describe the time to first AR. The influences of AUC and other covariates were explored using stepwise covariate modelling, bootstrap-stepwise covariate modelling and cross-validated stepwise covariate modelling. The clinical relevance of the effects was assessed with the time at which 90% of the patients were AR free (t90). RESULTS: Data from 87 patients (0.7-19.8 years old, 54 experiencing an AR) were analysed. The baseline hazard was described with a function changing in steps over time. No statistically significant covariate effects were identified, a finding substantiated by all methods used. Thus, within the observed AUC range (90% interval 1.13-8.40 h mg l⁻¹), a rise in AUC was not found to increase protection from AR. Dialysis time, sex and baseline weight were potential covariates, but the predicted clinical relevance of their effects was low. For the strongest covariate, dialysis time, median t90 was 5.8 days (90% confidence interval 5.1-6.8) for long dialysis times (90th percentile) and 7.4 days (6.4-11.7) for short dialysis times (10th percentile). CONCLUSIONS: A survival model with discrete time-varying hazards described the data. Within the observed range, AUC was not identified as a covariate. This feedback on clinical practice may help to avoid unnecessarily high CsA dosing in children.

Application of the optimal design approach to improve a pretransplant drug dose finding design for ciclosporin.

A time and sampling intensive pretransplant test dose design was to be reduced, but at the same time optimized so that there was no loss in the precision of predicting the individual pharmacokinetic (PK) estimates of posttransplant dosing. The following variables were optimized simultaneously: sampling times, ciclosporin dose, time of second dose, infusion duration, and administration order, using a published ciclosporin population PK model as prior information. The original design was reduced from 22 samples to 6 samples/patient and both doses (intravenous oral) were administered within 8 hours. Compared with the prior information given by the published ciclosporin population PK model, the expected standard deviations (SDs) of the individual parameters for clearance and bioavailability could be reduced by, on average, 40% under the optimized sparse designs. The gain of performing the original rich design compared with the optimal reduced design, considering the standard errors of the parameter estimates, was found to be minimal. This application demonstrates, in a practical clinical scenario, how optimal design techniques may be used to improve diagnostic procedures given available software and methods.

Long-term changes in cyclosporine pharmacokinetics after renal transplantation in children: evidence for saturable presystemic metabolism and effect of NR1I2 polymorphism.

To improve cyclosporine dose individualization, the authors carried out a comprehensive analysis of the effects of clinical and genetic factors on cyclosporine pharmacokinetics in 176 children before and up to 16 years after renal transplantation. Pretransplantation test doses of cyclosporine were given intravenously and orally, followed by blood sampling for 24 hours. After transplantation, cyclosporine was quantified at trough, 2 hours postdose, or with dose-interval curves. A 3-compartment population pharmacokinetic model was used to describe the data. Cyclosporine oral bioavailability increased more than 1.5-fold in the first month after transplantation, returning thereafter gradually to its initial value in 1 to 1.5 years. Moreover, older children receiving cyclosporine twice daily as the gelatin capsule microemulsion formulation had an about 1.25 to 1.3 times higher bioavailability than did the younger children receiving the liquid formulation thrice daily. In 91 children with genetic data after transplantation, patients carrying the NR1I2 g.-25385C-g.-24381A-g.-205_-200GAGAAG-g.7635G-g.8055C haplotype had about one-tenth lower bioavailability, per allele, than did noncarriers (P = .039). The significance of the NR1I2 genotype warrants further study. In conclusion, by accounting for the effects of developmental factors (body weight), time after transplantation, and cyclosporine dosing frequency/formulation, it may be possible to improve individualization of cyclosporine dosing in children.

[No thyroxin dose seemed sufficient--why?]. / Miksi mikään tyroksiiniannos ei tuntunut riittävän?

The health status of a woman with type 1 diabetes was followed during pregnancy in a maternity hospital. In addition to insulin, thyroxine therapy was applied due to hypothyreosis as a consequence of Basedow disease. Nephropathy and significant proteinuria had developed as complications of diabetes, with the proteinuria increasing considerably during pregnancy. Simultaneously thyroxine doses increased to exceptionally high levels. The cause of increasing doses was found to be secretion of thyroxine into urine. The phenomenon has been described earlier, but it is not generally recognized.

Pharmacogenetics of cyclosporine in children suggests an age-dependent influence of ABCB1 polymorphisms.

OBJECTIVE: To evaluate whether variations in the ABCB1, ABCC2, SLCO1B1, CYP3A4, CYP3A5, or NR1I2 genes are associated with the pharmacokinetics of cyclosporine in pediatric renal transplant candidates, and whether the effects of these variants are related to age. METHODS: A total of 104 pediatric patients (aged 0.36-16.3 years) were genotyped for 17 putatively functionally significant sequence variations in the ABCB1, SLCO1B1, ABCC2, CYP3A4, CYP3A5, and NR1I2 genes. The patients had undergone a pharmacokinetic study with intravenous and oral ciclosporine (INN, cyclosporin) before renal transplantation. RESULTS: In the whole population, the mean+/-SD cyclosporine oral bioavailability was 0.38+/-0.09, volume of distribution was 2.3+/-0.54 l/kg, and systemic clearance normalized by allometric body weight was 0.88+/-0.16 l/h/kg3/4. The prehepatic extraction ratio was 0.51+/-0.13, and the hepatic extraction ratio was 0.24+/-0.04, the former explaining 95% of the variability in oral bioavailability (P<0.0001). In children older than 8 years, the pre-hepatic extraction was 0.64+/-0.09 in those with the ABCB1 c.2677GG genotype, 0.52+/-0.11 in those with the c.2677GT genotype, and 0.41+/-0.03 in those with the c.2677TT genotype (P=0.021, r2=0.334), leading to corresponding differences in oral bioavailability (0.28+/-0.07, 0.36+/-0.07, and 0.44+/-0.04, respectively; P=0.012, r2=0.372). Similar associations were observed with the ABCB1 c.1236C>T variant and the related haplotype c.1199G-c.1236C-c.2677G-c.3435C (P<0.05). The estimated oral dose requirement and clearance of cyclosporine remained largely unexplained by the genetic variations. CONCLUSIONS: Although these data suggest an age-related effect of ABCB1 polymorphism on oral bioavailability, further studies are required on the predictive value of genotyping for individualization of cyclosporine dosing in children.

Cyclosporine A monitoring--how to account for twice and three times daily dosing.

Cyclosporine A (CsA) dose-interval pharmacokinetic profiles, performed 1-4 years post-transplantation, were collected from 74 renal transplanted children. Forty patients were on three times daily dosing (t.i.d.) and 34 on twice daily dosing (b.i.d.). Regression models for prediction of area under the curve (AUC) using 1-3 concentration time points as independent variables were developed. With similar weight-adjusted single doses (mg kg(-1)) of CsA, t.i.d. dosing resulted in a trough-concentration (C0) similar to that from b.i.d. dosing, but a 30% lower 2 h post-dose concentration (C2). For b.i.d. dosing the relationship between C0 and AUC was poor (r2=0.23) and the prediction error was large (5.8+/-33.5%). For t.i.d. dosing the relationship was better (r2=0.79), but prediction error was still large (4.5+/-24.9%). For C2 relationships were similar to those for the b.i.d. (r2=0.59) and t.i.d. (r2=0.63) groups, but explained modestly the variations of AUC (prediction error=2.6+/-16.8% b.i.d., 4.8+/-23.2% t.i.d.). Both C0 and C2 are useful monitoring methods when CsA is administered t.i.d. If the aim is similar specified daily drug exposure, the target C2 should be roughly 30% smaller in t.i.d. dosing than in b.i.d. dosing and the target C0 could be similar. The prediction error of AUC can be large in individual patients when using single time-point determinations, however. The use of multiple time points reduces the variation, but is less feasible.