Dataset Information

Population pharmacokinetic-pharmacodynamic analysis of voriconazole and anidulafungin in adult patients with invasive aspergillosis.

ABSTRACT: To evaluate the exposure-response relationships for efficacy and safety of voriconazole and anidulafungin in adult patients with invasive aspergillosis (IA), a population pharmacokinetic-pharmacodynamic (PK-PD) analysis was performed with data from a phase 3, prospective, double-blind, comparative study evaluating voriconazole and anidulafungin combination therapy versus voriconazole (and placebo) monotherapy. Anidulafungin/placebo treatment duration was 2 to 4 weeks, and voriconazole treatment duration was 6 weeks. Efficacy (6-week all-causality mortality and 6-week global response [n = 176]) and safety (hepatic [n = 238], visual [n = 199], and psychiatric [n = 183] adverse events [AEs]) endpoints were analyzed separately using a binary logistic regression model. In IA patients receiving voriconazole monotherapy, no positive associations between voriconazole exposure and efficacy or safety were identified. In IA patients receiving combination therapy, no positive associations between voriconazole or anidulafungin exposures and efficacy were identified. The 6-week survival rate tended to increase as anidulafungin treatment duration increased; this finding should be considered with caution. Additionally, in IA patients receiving combination therapy, a positive association between voriconazole and anidulafungin exposures (area under the curve [AUC] and trough concentration [C(min)]) and hepatic AEs was established; a weak positive association between voriconazole exposure (AUC and C(min)) and psychiatric AEs was also established, but no association between voriconazole exposure and visual AEs was identified. Besides the drug exposures, no other covariates (i.e., CYP2C19 genotype status, age, weight, body mass index, sex, race, or neutropenia status) were identified as significant predictors of the efficacy and safety endpoints in IA patients. This study was registered on ClinicalTrials.gov (NCT00531479).

SUBMITTER: Liu P

PROVIDER: S-EPMC4126689 | biostudies-literature | 2014 Aug

REPOSITORIES: biostudies-literature

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Population pharmacokinetic-pharmacodynamic analysis of voriconazole and anidulafungin in adult patients with invasive aspergillosis.

Liu Ping P Mould Diane R DR

Antimicrobial agents and chemotherapy 20140609 8

To evaluate the exposure-response relationships for efficacy and safety of voriconazole and anidulafungin in adult patients with invasive aspergillosis (IA), a population pharmacokinetic-pharmacodynamic (PK-PD) analysis was performed with data from a phase 3, prospective, double-blind, comparative study evaluating voriconazole and anidulafungin combination therapy versus voriconazole (and placebo) monotherapy. Anidulafungin/placebo treatment duration was 2 to 4 weeks, and voriconazole treatment ...[more]

PMID: 24914120

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Project description:OBJECTIVE:According to a recent randomized, double-blind clinical trial comparing the combination of voriconazole and anidulafungin (VOR+ANI) with VOR monotherapy for invasive aspergillosis (IA) in patients with hematologic disease or with hematopoietic stem cell transplant, mortality was lower after 6 weeks with VOR+ANI than with VOR monotherapy in a post hoc analysis of patients with galactomannan-based IA. The objective of this study was to compare the cost-effectiveness of VOR+ANI with VOR, from the perspective of hospitals in the Spanish National Health System. METHODS:An economic model with deterministic and probabilistic analyses was used to determine costs per life-year gained (LYG) for VOR+ANI versus VOR in patients with galactomannan-based IA. Mortality, adverse event rates, and life expectancy were obtained from clinical trial data. The costs (in 2015 euros [€]) of the drugs and the adverse event-related costs were obtained from Spanish sources. A Tornado plot and a Monte Carlo simulation (1,000 iterations) were used to assess uncertainty of all model variables. RESULTS:According to the deterministic analysis, for each patient treated with VOR+ANI compared with VOR monotherapy, there would be a total of 0.348 LYG (2.529 vs 2.181 years, respectively) at an incremental cost of €5,493 (€17,902 vs €12,409, respectively). Consequently, the additional cost per LYG with VOR+ANI compared with VOR would be €15,785. Deterministic sensitivity analyses confirmed the robustness of these findings. In the probabilistic analysis, the cost per LYG with VOR+ANI was €15,774 (95% confidence interval: €15,763-16,692). The probability of VOR+ANI being cost-effective compared with VOR was estimated at 82.5% and 91.9%, based on local cost-effectiveness thresholds of €30,000 and €45,000, respectively. CONCLUSION:According to the present economic study, combination therapy with VOR+ANI is cost-effective as primary therapy of IA in galactomannan-positive patients in Spain who have hematologic disease or hematopoietic stem cell transplant, compared with VOR monotherapy.

Project description:BackgroundVoriconazole is well established as standard treatment for invasive aspergillosis (IA). In 2017, isavuconazole, a new antifungal from the azole class, with a broader pathogen spectrum, was introduced in Sweden. A model has therefore been developed to compare the cost-effectiveness of isavuconazole and voriconazole in the treatment of possible IA in adults in Sweden.MethodsThe cost-effectiveness of isavuconazole versus voriconazole was evaluated using a decision-tree model. Patients with possible IA entered the model, with 6% assumed to actually have mucormycosis. It was also assumed that pathogen information would become available during the course of treatment for only 50% of patients, with differential diagnosis unavailable for the remainder. Patients who were considered unresponsive to first-line treatment were switched to second-line treatment with liposomal amphotericin-B. Data and clinical definitions included in the model were taken from the published randomised clinical trial comparing isavuconazole with voriconazole for the treatment of IA and other filamentous fungi (SECURE) and the single-arm, open-label trial and case-control analysis of isavuconazole for the treatment of mucormycosis (VITAL). A probabilistic sensitivity analysis was used to estimate the combined parameter uncertainty, and a deterministic sensitivity analysis and a scenario analysis were performed to test the robustness of the model assumptions. The model followed a Swedish healthcare payer perspective, therefore only considering direct medical costs.ResultsThe base case analysis showed that isavuconazole resulted in an incremental cost-effectiveness ratio (ICER) of 174,890 Swedish krona (SEK) per additional quality adjusted life-year (QALY) gained. This was mainly due to the efficacy of isavuconazole against IA and mucormycosis, as opposed to voriconazole, which is only effective against IA. Sensitivity and scenario analyses of the data showed that the average ICER consistently fell below the willingness to pay (WTP) threshold of 1,000,000 SEK. The probability of isavuconazole being cost-effective at a WTP of 170,000 SEK per QALY gained was 50% and at a WTP of 500,000 SEK per QALY gained was 100%.ConclusionsThis model suggests that the treatment of possible IA with isavuconazole is cost-effective compared with treatment with voriconazole from a Swedish healthcare payer perspective.

Project description:Cyclophosphamide (CPA) containing chemotherapy regimen is the standard of care for breast cancer treatment in sub-Saharan Africa. Wide inter-individual variations in pharmacokinetics (PK) of cyclophosphamide (CPA) influence the efficacy and toxicity of CPA containing chemotherapy. Data on the pharmacokinetics (PK) profile of CPA and its covariates among black African patients is lacking. We investigated population pharmacokinetic/pharmacogenetic/pharmacodynamic (PK-PG-PD) of CPA in Ethiopian breast cancer patients. During the first cycle of CPA-based chemotherapy, the population PK parameters for CPA were determined in 267 breast cancer patients. Absolute neutrophil count was recorded at baseline and day 20 post-CPA administration. A population PK and covariate model analysis was performed using non-linear mixed effects modeling. Semi-mechanistic and empiric drug response models were explored to describe the relationship between the area under concentration-time curve (AUC), and neutrophil toxicity. One compartment model better described CPA PK with population clearance and apparent volume of distribution (VD) of 5.41 L/h and 46.5 L, respectively. Inter-patient variability in CPA clearance was 54.5%. Patients carrying CYP3A5*3 or *6 alleles had lower elimination rate constant and longer half-life compared to wild type carriers. CYP2C9 *2 or *3 carriers were associated with increased clearance of CPA. Patients who received 500 mg/m2 based CPA regimen were associated with a 32.3% lower than average clearance and 37.1% lower than average VD compared to patients who received 600 mg/m2. A 0.1 m2 unit increase in body surface area (BSA) was associated with a 5.6% increment in VD. The mean VD (33.5 L) in underweight group (BMI < 18.5 kg/m2) was significantly lower compared to those of overweight (48.1 L) or obese patients (51.9 L) (p < 0.001). AUC of CPA was positively correlated with neutropenic toxicity. In conclusion, we report large between-patient variability in clearance of CPA. CYP3A5 and CYP2C9 genotypes, BSA, BMI, and CPA dosage regimen influence PK of CPA. Plasma CPA exposure positively predicts chemotherapy-associated neutropenic toxicity.

Dataset Information

Population pharmacokinetic-pharmacodynamic analysis of voriconazole and anidulafungin in adult patients with invasive aspergillosis.

Publications

Population pharmacokinetic-pharmacodynamic analysis of voriconazole and anidulafungin in adult patients with invasive aspergillosis.

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