Lamotrigine is the most widely used anti‐epileptic drug in pregnancy because of its low teratogenicity. However, there is an increased metabolism and clearance of lamotrigine in pregnancy contributing to suboptimal drug therapy and poor disease control, prompting the need for proactive dosage adjustments. The present study aimed to develop a pharmacometric model‐based framework for recommending an optimal dosage regimen for lamotrigine in pregnancy. A systematic review was performed to obtain aggregate data from the literature on the clearance of lamotrigine in pregnancy. The data were incorporated into simulations using PUMAS software to estimate the plasma concentrations at the preconception stage and during the 3 trimesters of pregnancy. Simulated drug exposures for different doses were investigated to ascertain plasma concentrations similar to the preconception value and above the minimum effective concentration. The simulated mean steady‐state trough plasma concentrations of lamotrigine were significantly decreased in pregnant women over the course of the 3 trimesters (3.17 ± 0.93 mg/L, 2.14 ± 0.86 mg/L, and 1.51 ± 0.65 mg/L, respectively), compared with non‐pregnant women (4.31 ± 1.14 mg/L) (P < .001). The simulation studies revealed that doses of 150 mg, 175 mg, 225 mg, and 250 mg twice daily in the preconception stage and the 3 trimesters, respectively, achieve the target concentrations. Thus, the model‐informed dosage regimen of lamotrigine proposed in this study shall be used to initiate appropriate dosing in pregnant women; however, the safety and efficacy of the drug must be assured through therapeutic drug monitoring in order to avoid therapeutic failure of lamotrigine in pregnancy.
AIMS 6 mercaptopurine (6MP) is the mainstay chemotherapy for acute lymphoblastic leukaemia (ALL) and is conventionally available as 50 mg tablets. This study aimed to evaluate the bioequivalence of a new 6MP Powder for Oral Suspension (PFOS) intended for paediatric use. Additionally, a virtual study with the obtained data was planned for determining a dose of the PFOS that matches tablet exposures and to confirm optimal drug levels in pediatrics. METHODS An open-label, randomized, two-treatment, two-period, two-sequence, single oral dose, crossover, bioequivalence study was conducted on 51 healthy subjects. A population pharmacokinetic (PopPK) model was developed using the data to perform simulations with various PFOS doses and select a bioequivalent dose. To simulate 6MP and 6 thioguanine (6TGN) exposures in pediatrics, a literature model for paediatric ALL patients, and allometrically scaled PK parameters were utilised. RESULTS The 6MP PFOS had 47% higher bioavailability compared to the reference product. Simulations using a two-compartmental PopPK model with dissolution and transit compartments showed that 40 mg of PFOS was found to be equivalent to the 50mg tablets. The simulated 6TGN concentrations in virtual paediatric patients were between 114 and 703.6 pmol/8x108 RBCs, which was within the range of values reported in paediatric ALL studies. CONCLUSION The study demonstrates that 40 mg dose of 6MP PFOS 10 mg/mL has the same extent of absorption as the 50 mg tablet which can be precisely administered in pediatrics. The study also demonstrates the role of modelling and simulation to perform virtual bioequivalence and paediatric studies.
Aim: Sepsis patients are more prone to have sub-therapeutic drug concentrations and so treatment failures. Non optimized dosage regimen of antibiotics is one of the prime reasons why the prevalence of antibiotic resistance is rising. This study aimed to propose optimized dosage regimen for Meropenem in sepsis patients using the pharmacometric approach. Methods: Prospective open label study was conducted among 58 south Indian adult Sepsis patients received Meropenem 1g over 30 mins or 3-hour infusion every 8h or 12h. The plasma samples were collected from the patients using window sampling (1-8 h) and concentration of Meropenem was quantified using RP-HPLC. Population pharmacokinetics analysis and simulations were performed using PUMAS® v.1.40.1. Results: Two compartment model with first order elimination best described the data and the total clearance (CL), inter-compartmental clearance (Q), volume of the central compartment (Vc), volume of the peripheral compartment (Vp) were 4.46 L/hr & 13.29 L/h and 47.16 L & 26.55 L respectively. The most significant covariate that influenced the Meropenem Clearance was creatinine clearance. The additive error was 0.0021 mg/L and the proportional error was 15.6%. Meropenem administered over 3 h infusion was observed to be superior than 30 min infusion by simulation studies. Conclusion: Renal function of the patients significantly influence the clearance of Meropenem and infusion over 3 h is found to be superior than 30 min in terms of attaining the trough concentration of 8 mg/L. Additionally, therapeutic drug monitoring of Meropenem in these patients will aid in the optimization of Meropenem dosing regimen.
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