Denise H. Fleming

A limited sampling strategy for tacrolimus in renal transplant patients

AIMS To develop and validate limited sampling strategy (LSS) equations to estimate area under the curve (AUC(0-12)) in renal transplant patients. METHODS Twenty-nine renal transplant patients (3-6 months post transplant) who were at steady state with respect to tacrolimus kinetics were included in this study. The blood samples starting with the predose (trough) and collected at fixed time points for 12 h were analysed by microparticle enzyme immunoassay. Linear regression analysis estimated the correlations of tacrolimus concentrations at different sampling time points with the total measured AUC(0-12). By applying multiple stepwise linear regression analysis, LSS equations with acceptable correlation coefficients (R(2)), bias and precision were identified. The predictive performance of these models was validated by the jackknife technique. RESULTS Three models were identified, all with R(2) > or = 0.907. Two point models included one with trough (C(0)) and 1.5 h postdose (C(1.5)), another with trough and 4 h postdose. Increasing the number of sampling time points to more than two increased R(2) marginally (0.951 to 0.990). After jackknife validation, the two sampling time point (trough and 1.5 h postdose) model accurately predicted AUC(0-12). Regression coefficient R(2) = 0.951, intraclass correlation = 0.976, bias [95% confidence interval (CI)] 0.53% (-2.63, 3.69) and precision (95% CI) 6.35% (4.36, 8.35). CONCLUSION The two-point LSS equation [AUC(0-12) = 19.16 + (6.75.C(0)) + (3.33.C1.5)] can be used as a predictable and accurate measure of AUC(0-12) in stable renal transplant patients prescribed prednisolone and mycophenolate.

A Reliable Limited Sampling Strategy for the Estimation of Mycophenolic Acid Area Under the Concentration Time Curve in Adult Renal Transplant Patients in the Stable Posttransplant Period

In renal transplant patients, there is an established relationship between mycophenolate area under the curve and clinical outcome. The authors have developed and validated a limited sampling strategy to estimate mycophenolic acid area under the curve to 12 hours (MPA AUC0-12) in a stable renal transplant Indian population prescribed a formulation of mycophenolate mofetil (Mofilet) along with prednisolone and tacrolimus. Intensive pharmacokinetic sampling was performed in 29 patients to measure mycophenolate concentration from trough to 12 hours postdose. Subsets of different timed concentrations against total measured 12-hour area under the curve were analyzed by linear regression. Three models were identified and linear regression analysis done. After all subset regression analysis, three, four, and five time point limited sampling strategies (LSS) were developed having correlation coefficients above 0.92. Validation of the models was performed using the jackknife method and their predictive performances were tested. After validation, the correlation coefficients for all three models were above 0.901. The five-point LSS had the best predictive performance with a bias (95% confidence interval) of 0.67% (-3.45 to 4.79) and mean precision 7.73%. In all patients except one, the five-point LSS estimation for total area under the curve was within ± 20% of the total measured AUC0-12. Trough concentration had a significant correlation with AUC0-12 (r2 = 0.69). However, if dosing in routine clinical practice was adjusted based only on trough concentration, 41% of our patients would require a different dose compared with monitoring using AUC0-12. The five-point LSS uses half-hourly samples from trough to 1.5 hour postdose with an additional sample at 3 hours. Ninety-three percent of our patients had a Cmax within 1.5 hour and inclusion of all the time points up to1.5 hour gave a better estimate of AUC0-12. This model simplifies area under the curve measurement with high precision in stable adult renal transplant patients.

A possible simplification for the estimation of area under the curve (AUC₀₋₁₂) of enteric-coated mycophenolate sodium in renal transplant patients receiving tacrolimus.

Enteric-coated mycophenolate sodium (EC-MPS) is widely used in renal transplantation. With a delayed absorption profile, it has not been possible to develop limited sampling strategies to estimate area under the curve (mycophenolic acid [MPA] AUC0-12), which have limited time points and are completed in 2 hours. We developed and validated simplified strategies to estimate MPA AUC0-12 in an Indian renal transplant population prescribed EC-MPS together with prednisolone and tacrolimus. Intensive pharmacokinetic sampling (17 samples each) was performed in 18 patients to measure MPA AUC0-12. The profiles at 1 month were used to develop the simplified strategies and those at 5.5 months used for validation. We followed two approaches. In one, the AUC was calculated using the trapezoidal rule with fewer time points followed by an extrapolation. In the second approach, by stepwise multiple regression analysis, models with different time points were identified and linear regression analysis performed. Using the trapezoidal rule, two equations were developed with six time points and sampling to 6 or 8 hours (8hrAUC[0-12exp]) after the EC-MPS dose. On validation, the 8hrAUC(0-12exp) compared with total measured AUC0-12 had a coefficient of correlation (r2) of 0.872 with a bias and precision (95% confidence interval) of 0.54% (-6.07-7.15) and 9.73% (5.37-14.09), respectively. Second, limited sampling strategies were developed with four, five, six, seven, and eight time points and completion within 2 hours, 4 hours, 6 hours, and 8 hours after the EC-MPS dose. On validation, six, seven, and eight time point equations, all with sampling to 8 hours, had an acceptable r2 with the total measured MPA AUC0-12 (0.817-0.927). In the six, seven, and eight time points, the bias (95% confidence interval) was 3.00% (-4.59 to 10.59), 0.29% (-5.4 to 5.97), and -0.72% (-5.34 to 3.89) and the precision (95% confidence interval) was 10.59% (5.06-16.13), 8.33% (4.55-12.1), and 6.92% (3.94-9.90), respectively. Of the eight simplified approaches, inclusion of seven or eight time points improved the accuracy of the predicted AUC compared with the actual and can be advocated based on the priority of the user.

Pharmacokinetics of concentration-controlled mycophenolate mofetil in proliferative lupus nephritis: an observational cohort study.

Background: Mycophenolate mofetil (MMF) has variable pharmacokinetics. This study examines the pharmacokinetic and clinical correlations in proliferative lupus nephritis. Methods: Thirty-four patients were started on MMF, and the area under the concentration–time curve (AUC) was measured by limited sampling strategies, and dosing was adjusted to achieve an AUC of 30–60 mg·h·L−1. Twenty-seven patients had at least 2 measurements, and renal response was assessed within 1 year. Results: About 61.8% of patients had mycophenolic acid (MPA) AUC <30 mg·h·L−1 with an empiric starting dose of 30 mg/kg. About 79.4% of patients achieved renal response by 1 year, and the median time to renal response was 111 days. MMF dose per body weight had a weak correlation with the AUC and did not correlate with trough concentrations. The median dose was 1.5 g/d at entry and 2 g/d after dose modification during the induction phase. Trough concentrations had a weak correlation with AUC. Patients with serum albumin ≥35 g/L had a greater chance of having an AUC ≥30 mg·h·L−1. The between-patient coefficient of variability for dose-normalized AUC was 37.9% at entry and 31% within 1 year, whereas repeated measurements over time in an individual had a good intraclass correlation of 0.78. Infections occurred in 11.8% and toxicities in 5.9%. MPA exposure was not significantly associated with adverse events. Patients with an AUC ≥30 mg·h·L−1 had greater renal response at 1 year. Conclusions: Lupus nephritis patients induced with concentration-controlled MMF had excellent renal response and fewer adverse events with lower than usual dosing. MPA exposure had high interpatient variability, requiring measurements for personalized dosing, and fewer adverse events. Long-term cost reduction is achievable with lower doses and good renal response in the majority of patients.

Therapeutic Drug Monitoring of Levetiracetam and Lamotrigine: Is There a Need?

Background: This study was a retrospective assessment of the therapeutic drug monitoring data collected for levetiracetam and lamotrigine from a clinical setting. The proportion of patients in relation to the therapeutic ranges for serum concentrations of lamotrigine and levetiracetam was estimated, and the influence of age and anticonvulsant comedications on their clearances were studied. Methods: Information on levetiracetam (2011–2013) and lamotrigine (2008–2013) dose, trough concentration, age, sex, body weight, and anticonvulsant comedications prescribed was obtained from the therapeutic drug monitoring register and archived medical records. Patients were categorized into 4 groups based on anticonvulsant comedications and further divided into 3 subgroups based on age (a: <9 years; b: 9–17 years; c: ≥18 years). In each subgroup, the proportion of patients who achieved trough concentrations in the therapeutic range for levetiracetam and lamotrigine was computed. Apparent clearance (CL/F) was compared across subgroups by 1-way analysis of variance, and factors which significantly predicted CL/F were identified by stepwise multiple linear regression. Results: Overall, 348 (330 patients) and 706 (493 patients) samples for levetiracetam and lamotrigine were included in the analysis. Of these, 56.9% and 72.4% were within, 43.1% and 23.9% below, 0% and 3.7% above the therapeutic range for levetiracetam and lamotrigine, respectively. A significant difference in CL/F was noted across subgroups for levetiracetam (P < 0.001) and lamotrigine (P < 0.001). Age <9 years, age ≥18 years, and inducer comedications significantly predicted CL/F for levetiracetam. For lamotrigine, inhibitor comedications, age <9 years, inducer comedications, and age 9–17 years significantly predicted CL/F. Conclusions: These findings emphasize the need to monitor relatively newer anticonvulsants, lamotrigine and levetiracetam, especially among children and when other anticonvulsant comedications are prescribed or discontinued in the treatment regimen.

An initial experience with therapeutic drug monitoring of levetiracetam as reported from a pediatric clinical setting in India

BACKGROUND AND OBJECTIVES Monitoring of levetiracetam in routine clinical practice is not strongly recommended. The aim of this study was to investigate any difference in serum levetiracetam concentration between patients on enzyme-inducing and -inhibiting antiepileptic co-medication and also to identify any correlation between levetiracetam concentration and clinical response. MATERIALS AND METHODS This study included pediatric patients with epilepsy from a tertiary care referral hospital in India. Details of antiepileptic co-medication, seizure frequency before and after initiating levetiracetam were recorded. Serum trough levetiracetam concentration was measured. RESULTS Of the 69 children recruited in the study, 55 children had >50% reduction in seizure frequency compared to baseline seizure frequency. Eight patients showed no improvement. The serum concentration of levetiracetam was more than 10 μg/ml in 78.2% of responders and 75% non-responders. There was no difference in dosing between responders and non-responders. Patients on enzyme-inducing co-medication had lower median serum levetiracetam concentrations (7.3 μg/ml) compared to those on enzyme-inhibiting co-medication (14.4 μg/ml) or those without interfering antiepileptic co-medication (16.6 μg/ml). CONCLUSION Levetiracetam monitoring has a role in patients on antiepileptic polypharmacy and for confirmation of compliance.

A Nonparametric Pharmacokinetic Approach to Determine the Optimal Dosing Regimen for 30-Minute and 3-Hour Meropenem Infusions in Critically Ill Patients.

Background: Pharmacokinetics of meropenem differ widely in the critically ill population. It is imperative to maintain meropenem concentrations above the inhibitory concentrations for most of the interdose interval. A population pharmacokinetic/pharmacodynamic model was developed to determine the probability of target attainment for 3-hour and 30-minute infusion regimens in this population. Methods: This study was performed in an intensive care setting among adult patients who were initiated on meropenem at a dose of 1000 mg. Multiple blood specimens were collected at predetermined time points during the interdose period, and meropenem concentrations were measured using high performance liquid chromatography. Using Pmetrics, a pharmacokinetic/pharmacodynamic model was developed and validated. Monte Carlo simulation was performed, and probability of target attainment (100% T > minimum inhibitory concentration (MIC), with a probability >0.9) for doubling MICs was determined for different regimens of meropenem. Results: A 2-compartment multiplicative gamma error model best described the population parameters from 34 patients. The pharmacokinetic parameters used in the final model were Ke (elimination rate constant from the central compartment), Vc (volume of distribution of central compartment), KCP and KPC (intercompartmental rate constants), and IC2 (the fitted amount of meropenem in the peripheral compartment). Inclusion of creatinine clearance (CLcreat) and body weight as covariates improved the model prediction (Ke = Ke0 × , Vc = Vc0 × Weight0.5). The Ke and Vc [geometric mean (range)] of the individuals were 0.54 (0.01–2.61)/h and 9.36 (4.35–21.62) L, respectively. The probability of attaining the target, T > MIC of 100%, was higher for 3-hour infusion regimens compared with 30-minute infusion regimens for all ranges of CLcreat. Conclusions: This study emphasizes that extended regimens of meropenem are preferable for treating infections caused by bacteria with higher MICs. The nonparametric analysis using body weight and CLcreat as covariate adequately predicted the pharmacokinetics of meropenem in critically ill patients with a wide range of renal function.

Estimation of Monocrotophos renal elimination half-life in humans

Abstract Introduction. Monocrotophos, implicated in about 1/4th of organophosphate poisonings in our centre, is associated with the highest mortality (24%). Yet data on its pharmacokinetics in humans is limited. We estimated the renal elimination half-life of monocrotophos. Patients and Methods. Consecutive patients presenting with monocrotophos overdose over a 2-month period who had normal renal function were recruited. Monocrotophos in plasma and urine were quantitated by high-performance liquid chromatography. Urine was obtained from catheterised samples at 0–2, 2–4, 4–6, 6–8, 8–12 and 12–24 h. Plasma specimens were collected at the time of admission, and at the midpoint of the urine sample collections at 1, 3, 5, 7, 10, 15 and 21 h. Renal elimination half-life was calculated from the cumulative amount excreted in the urine. Results. The cohort of 5 male patients, aged 35.8 ± 2.94 years, presented with typical organophosphate (cholinergic) toxidrome following intentional monocrotophos overdose. All patients required mechanical ventilation; one patient died. Plasma data was available from 5 patients and urine data from 3 patients. The median renal elimination half-life was 3.3 (range: 1.9–5.0 h). Plasma monocrotophos values, as natural log, fell in a linear fashion up to around 10 h after admission. After the 10-hour period, there was a secondary rise in values in all the 3 patients in whom sampling was continued after 10 h. Conclusion. A renal elimination half-life of 3.3 h for monocrotophos is consistent with a water-soluble compound which is rapidly cleared from the plasma. The secondary rise in plasma monocrotophos values suggests possible re-distribution. Determining the elimination profile of this compound will help develop better strategies for treatment.

Mycophenolic acid area under the curve recovery time following rifampicin withdrawal.

Renal transplant patients prescribed mycophenolate mofetil (MMF) may require treatment for tuberculosis with a regimen including the tuberculocidal drug rifampicin. MMF is an ester prodrug which is rapidly hydrolysed to the active compound, mycophenolic acid (MPA). Therapeutic drug monitoring of mycophenolate involves the measurement of MPA area under the curve (MPA-AUC0-12). Rifampicin is known to increase the metabolism and decrease enterohepatic recirculation of mycophenolic acid, (MPA). When MPA is monitored after the discontinuation of rifampicin, an important factor is the time required for the MPA area under the curve to return to the pre-rifampicin value. At present this is not known. This report describes one such renal allograft patient, on long term MMF and prescribed rifampicin by a local physician. As expected there was a clinically significant decrease in MPA-AUC0-12 Three weeks after rifampicin was discontinued the MPA-AUC0-12 was still only 65% of the pre-rifampicin value and only 55% of the steady state MPA-AUC0-12 measured six months later.

Cisplatin Concentrations in Long and Short Duration Infusion: Implications for the Optimal Time of Radiation Delivery

INTRODUCTION Cisplatin has radiosensitizing properties and the best sensitization to radiotherapy occurs with a higher plasma concentration of cisplatin. To our knowledge the optimal time sequence between chemotherapy and administration of radiation therapy, to obtain maximum effect from concurrent chemoradiation is unclear. AIM The aim of this study was to measure the two cisplatin infusion regimens in order to determine the total and free cisplatin post infusion concentration changes over time. These changes may have clinical implications on the optimum time of administration of post infusion radiation therapy. MATERIALS AND METHODS Two cohorts of patients were recruited and both, total and free plasma concentration of cisplatin following long and short durations of intravenous infusion was determined. Blood samples were collected at 0.5, 1, 1.5, 2, 3 and 5 hours from the start of the infusion in the 1hour infusion group and at 2, 3, 3.5, 4, 6 and 24 hours from the start of the infusion, in the 3 hour infusion group. Total and free cisplatin concentrations were measured using a validated HPLC-UV method. RESULTS The highest concentration of total and free cisplatin was achieved at the end of the infusion in both regimens. Total cisplatin concentration declined 30 minutes after the end of infusion in both the groups. After 1hour of discontinuing cisplatin, the free cisplatin concentration also declined significantly. CONCLUSION We conclude that radiation should be administered within 30 minutes of completion of the infusion irrespective of the duration of infusion.