Population pharmacokinetics of oxcarbazepine active metabolite in Chinese paediatric epilepsy patients and its application in individualised dosage regimens.

PURPOSE: Oxcarbazepine (OXC) is an antiepileptic drug metabolised to active 10-monohydroxy derivative (MHD) following oral administration. There are no MHD population pharmacokinetic (PPK) models that describe the influence of genetic factors on MHD pharmacokinetics (PK). We developed a PPK model of MHD to investigate gene polymorphism of enzymes associated with MHD PK in Chinese paediatric epilepsy patients and evaluated its utility for dose individualisation. METHODS: Data were prospectively collected from 141 paediatric epilepsy patients (aged ≤ 14 years) who received OXC therapy at the First Affiliated Hospital of Fujian Medical University. The trough concentrations at steady state were determined by enzyme-multiplied immunoassay. Patients were genotyped for four single nucleotide polymorphisms (UGT2B7 802T>C, UGT1A9 I399C>T, ABCB1 3435C>T, and ABCB2 1249G>A). Patient gender, age, body weight (BW), hepatorenal function, and co-administrations were recorded. The PPK model was developed using nonlinear mixed-effects modelling software. The clinical performance of the final model was evaluated by including additional paediatric patients (n = 20) in the validation group. RESULTS: Oral clearance of MHD was significantly influenced by BW. The MHD PK was unrelated to the other covariates, such as the four single nucleotide polymorphisms and co-administration with new-generation antiepileptic drugs. The final BW-dependent exponent model showed the best fit with our data and predicted the trough concentrations in the validation group more accurately than the basic model. A new dosing strategy combining the dosage guideline and Bayesian method is proposed to individualise OXC regimens. CONCLUSION: A PPK model was established to estimate individual MHD clearance in paediatric patients taking OXC to develop individualised OXC dosing regimens for Chinese paediatric epilepsy patients.

Cost-effectiveness analysis of genotype screening and therapeutic drug monitoring in patients with inflammatory bowel disease treated with azathioprine therapy: a Chinese healthcare perspective using real-world data.

BACKGROUND: This study aimed to analyze the cost-effectiveness of combining screening for thiopurine methyl transferase (TPMT) and nucleotide triphosphate diphosphatase (NUDT15) defective alleles with therapeutic drug monitoring (TDM) in Chinese patients with inflammatory bowel disease (IBD) treated with azathioprine (AZA). METHODS: We evaluated the cost-effectiveness of combining screening for NUDT15 and TPMT deficiency with TDM in patients receiving AZA treatment over a 1-year horizon by developing a decision tree model. Real-world data and published literature were used to derive model inputs. The model's primary outcomes included quality-adjusted life-years (QALYs) and incremental cost-effectiveness ratios (ICERs). One-way and probabilistic sensitivity analyses were used to address uncertainty. RESULTS: Compared to NUDT15 genotyping, the combined TPMT/NUDT15 genotyping strategy cost an additional $13.83, yielding an ICER of $3,929.54/QALY, which was under the willingness-to-pay level of $30,425 per QALY in China. Compared to strategies with singular TPMT genotyping or no genotyping, the combined TPMT/NUDT15 genotyping strategy gained 0.00406 and 0.00782 QALYs and reduced the cost by $25.15 and $99.06, respectively. Additionally, incorporating TDM of AZA was more effective and less expensive than strategies without TDM. One-way sensitivity analysis revealed the expense attached to severe myelotoxicity to be the factor with the greatest influence in the present research. The application of the combined genotype screening strategy with TDM of AZA treatment was found to have a 91.7% chance of being cost-effective. CONCLUSIONS: For Chinese patients with IBD who receive an AZA regimen, a strategy involving combined NUDT15/TPMT genotype screening prior to treatment initiation and incorporating TDM for treatment management is cost-effective compared to strategies involving genotyping of NUDT15 or TPMT alone or genotyping without TDM.

First-line Treatment with Ribociclib plus Endocrine Therapy for Premenopausal Women with Hormone-receptor-positive Advanced Breast Cancer: A Cost-effectiveness Analysis.

BACKGROUND: We conducted a cost-effectiveness analysis incorporating recent phase III clinical trial (MONALEESA-7) data to evaluate the cost-effectiveness of ribociclib (RIB) as a first-line treatment for premenopausal women with hormone receptor (HR)-positive and human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer (ABC) from the United States healthcare payer perspective. In addition, because RIB has not been marketed in China, we identified the range of drug costs for which RIB could be considered cost effective from a Chinese healthcare system perspective. PATIENTS AND METHODS: A Markov model was developed to evaluate the cost-effectiveness of adding RIB to endocrine therapy over a lifetime. The clinical outcomes and utility data were obtained from published literature. Costs data were obtained from United States and Chinese official websites, and we determined the potential price for RIB in China based on its price in the United States. The main outcomes of this study were the incremental cost-effectiveness ratio (ICER) and quality-adjusted life-years (QALYs). RESULTS: The model projected that mean outcome was better with RIB and endocrine combined (3.83366 QALYs) than with endocrine therapy alone (2.71203 QALYs). In the United States, RIB and endocrine therapy cost an additional $604,960.06, resulting in an ICER of $539,357.95/QALY compared with endocrine monotherapy. Subgroup analyses indicated that, in China, the projected mean outcomes were better for RIB and endocrine therapy (6.37 QALYs) than for endocrine monotherapy (2.71 QALYs). The corresponding incremental costs were $224,731.88943. Thus, the ICER comparing RIB and endocrine therapy with endocrine therapy alone represented a $61,454.96/QALY gain. CONCLUSION: Additional use of RIB is estimated to not be cost effective as a first-line treatment for premenopausal women with HR-positive, HER2-negative ABC in the United States. A value-based price for the cost of RIB is less than $31.74/200 mg for China.

Population pharmacokinetics of azathioprine active metabolite in patients with inflammatory bowel disease and dosage regimens optimisation.

Azathioprine is a first-line drug used to maintain the remission of inflammatory bowel disease (IBD). As a prodrug, azathioprine is metabolised to produce active 6-thioguanine nucleotides (6-TGN). There are large individual variations in the pharmacokinetics/pharmacodynamics of 6-TGN in patients with IBD. Here, we aimed to develop a model to quantitatively investigate factors that affect 6-TGN pharmacokinetics to formulate a dosage guideline for azathioprine. Data were collected prospectively from 100 adult patients with IBD who were receiving azathioprine. Patients were genotyped for two single-nucleotide polymorphisms (TPMT*3C c.719A > G and NUDT15 c.415C > T). Using high-performance liquid chromatography, we measured 156 steady-state trough concentrations of 6-TGN within the range 0.09 to 1.16 mg/L (ie 133-1733 pmol per 8 × 108 RBC). The covariates analysed included sex, age, body-weight, laboratory tests and concomitant medications. A population pharmacokinetic model was established using "non-linear mixed-effects modelling" software and the "first-order conditional estimation method with interaction." Body-weight, TPMT*3C polymorphisms and co-therapy with mesalazine were found to be important factors influencing the clearance of 6-TGN. A dosage guideline for azathioprine was developed based on the PPK model that enables individualised azathioprine dosing in adult patients with different body-weights, TPMT*3C genotypes and co-administration with mesalazine.

Cost-effectiveness of atezolizumab plus chemotherapy for advanced non-small-cell lung cancer.

Background Adding atezolizumab to carboplatin/nab-paclitaxel improved progression-free survival and overall survival in patients with advanced non-squamous non-small-cell lung cancer. However, estimating the economy of atezolizumab/carboplatin/nab-paclitaxel is urgent on account of the high cost of atezolizumab. Objective This study aimed to evaluate the cost-effectiveness of atezolizumab plus carboplatin/nab- paclitaxel for untreated advanced non-squamous non-small-cell lung cancer from the United States payer perspective. Setting This study was based on randomized clinical trial data from the IMpower130 (NCT02367781) published in Lancet Oncology (May 2019). Method A Markov model was constructed to estimate the health expenditure on atezolizumab in combination with carboplatin/nab-paclitaxel for advanced non-small-cell lung cancer treatment. Drug costs were collected from Red Book Wholesale Acquisition Cost, and health state utility values were obtained from the literature. Uncertainty was evaluated via one-way and probabilistic sensitivity analyses. Main outcome measure The main outcomes were cost, life years, quality-adjusted life years, and incremental cost-effectiveness ratio. Results Over a 10-year horizon, atezolizumab/carboplatin/nab-paclitaxel treatment was associated with an expected 1.76 life years and 0.99 quality-adjusted life years compared to the 1.21 life years and 0.67 quality-adjusted life years for carboplatin/nab-paclitaxel alone. Compared to carboplatin/nab-paclitaxel, atezolizumab/carboplatin/nab-paclitaxel produced an incremental cost of $105,617. The resultant incremental cost-effectiveness ratio was $333,199 per quality-adjusted life year, which exceeded the willingness-to-pay threshold of $180,000 per quality-adjusted life year. The price of atezolizumab and utility values were the parameters that greatly impacted the incremental cost-effectiveness ratio. Carboplatin/nab-paclitaxel exhibited 98.6% probability of being a cost-effective treatment option compared to atezolizumab/carboplatin/nab-paclitaxel at a willingness-to-pay of $180,000 per quality-adjusted life year. However, reducing atezolizumab acquisition cost by 43.4% could make atezolizumab/carboplatin/nab-paclitaxel more cost-effective than carboplatin/nab-paclitaxel. Conclusion Adding atezolizumab to carboplatin/nab-paclitaxel was not cost-effective for advanced non-squamous non-small-cell lung cancer in the base-case scenario. Decreasing atezolizumab acquisition cost might enhance the cost-effectiveness.