Semimechanistic Bone Marrow Exhaustion Pharmacokinetic/Pharmacodynamic Model for Chemotherapy-Induced Cumulative Neutropenia.

Paclitaxel is a commonly used cytotoxic anticancer drug with potentially life-threatening toxicity at therapeutic doses and high interindividual pharmacokinetic variability. Thus, drug and effect monitoring is indicated to control dose-limiting neutropenia. Joerger et al. (2016) developed a dose individualization algorithm based on a pharmacokinetic (PK)/pharmacodynamic (PD) model describing paclitaxel and neutrophil concentrations. Furthermore, the algorithm was prospectively compared in a clinical trial against standard dosing (Central European Society for Anticancer Drug Research Study of Paclitaxel Therapeutic Drug Monitoring; 365 patients, 720 cycles) but did not substantially improve neutropenia. This might be caused by misspecifications in the PK/PD model underlying the algorithm, especially without consideration of the observed cumulative pattern of neutropenia or the platinum-based combination therapy, both impacting neutropenia. This work aimed to externally evaluate the original PK/PD model for potential misspecifications and to refine the PK/PD model while considering the cumulative neutropenia pattern and the combination therapy. An underprediction was observed for the PK (658 samples), the PK parameters, and these parameters were re-estimated using the original estimates as prior information. Neutrophil concentrations (3274 samples) were overpredicted by the PK/PD model, especially for later treatment cycles when the cumulative pattern aggravated neutropenia. Three different modeling approaches (two from the literature and one newly developed) were investigated. The newly developed model, which implemented the bone marrow hypothesis semiphysiologically, was superior. This model further included an additive effect for toxicity of carboplatin combination therapy. Overall, a physiologically plausible PK/PD model was developed that can be used for dose adaptation simulations and prospective studies to further improve paclitaxel/carboplatin combination therapy.

Validation of a Commercial Assay and Decision Support Tool for Routine Paclitaxel Therapeutic Drug Monitoring (TDM).

BACKGROUND: The value of therapeutic drug monitoring (TDM) for paclitaxel (PTX) was recently demonstrated in the largest TDM trial ever conducted in oncology. The trial demonstrated significant reduction in neuropathy when using TDM. Dose adjustment for PTX was based on time above a threshold concentration (Tc>0.05). Tc>0.05 must be calculated with a pharmacokinetic model and complex nonlinear mixed-effects software. The use of the software and chromatographic methods to measure PTX requires specialized expertise. User-friendly methods to quantitate PTX and calculate Tc>0.05 could simplify the introduction of TDM into routine clinical practice. METHODS: The immunoassay (MyPaclitaxel) was used to quantitate PTX in samples from the clinical trial; the results were used to calculate Tc>0.05 using a stand-alone computer program with a simple, friendly graphical user interface for nonlinear mixed-effects pharmacokinetic calculations (MyCare Drug Exposure Calculator). The resulting dose recommendations from the calculated Tc>0.05 were compared with those using liquid chromatography-ultraviolet detection and NONMEM to examine the efficacy of the simpler tools for TDM. RESULTS: There was a good agreement between the immunoassay and liquid chromatography-ultraviolet detection: Passing-Bablok regression slope was 1.045 and intercept was -6.00, R was 0.9757, and mean bias was -1.77 ng/mL (-2.07 nmol/L). Dosing recommendations were identical for 70% of the cycles and within 10% for 89% of the samples. All Tc>0.05 values were at the same or adjacent medical decision points. CONCLUSIONS: MyPaclitaxel assay and MyCare Drug Exposure Calculator are convenient, user-friendly tools that may be suitable for routine TDM of PTX in clinical care.

Excel-Based Tool for Pharmacokinetically Guided Dose Adjustment of Paclitaxel.

BACKGROUND: Neutropenia is a frequent and severe adverse event in patients receiving paclitaxel chemotherapy. The time above a paclitaxel threshold concentration of 0.05 µmol/L (Tc > 0.05 µmol/L) is a strong predictor for paclitaxel-associated neutropenia and has been proposed as a target pharmacokinetic (PK) parameter for paclitaxel therapeutic drug monitoring and dose adaptation. Up to now, individual Tc > 0.05 µmol/L values are estimated based on a published PK model of paclitaxel by using the software NONMEM. Because many clinicians are not familiar with the use of NONMEM, an Excel-based dosing tool was developed to allow calculation of paclitaxel Tc > 0.05 µmol/L and give clinicians an easy-to-use tool. METHODS: Population PK parameters of paclitaxel were taken from a published PK model. An Alglib VBA code was implemented in Excel 2007 to compute differential equations for the paclitaxel PK model. Maximum a posteriori Bayesian estimates of the PK parameters were determined with the Excel Solver using individual drug concentrations. Concentrations from 250 patients were simulated receiving 1 cycle of paclitaxel chemotherapy. Predictions of paclitaxel Tc > 0.05 µmol/L as calculated by the Excel tool were compared with NONMEM, whereby maximum a posteriori Bayesian estimates were obtained using the POSTHOC function. RESULTS: There was a good concordance and comparable predictive performance between Excel and NONMEM regarding predicted paclitaxel plasma concentrations and Tc > 0.05 µmol/L values. Tc > 0.05 µmol/L had a maximum bias of 3% and an error on precision of <12%. The median relative deviation of the estimated Tc > 0.05 µmol/L values between both programs was 1%. CONCLUSIONS: The Excel-based tool can estimate the time above a paclitaxel threshold concentration of 0.05 µmol/L with acceptable accuracy and precision. The presented Excel tool allows reliable calculation of paclitaxel Tc > 0.05 µmol/L and thus allows target concentration intervention to improve the benefit-risk ratio of the drug. The easy use facilitates therapeutic drug monitoring in clinical routine.

Single-dose pharmacokinetics of cidofovir in continuous venovenous hemofiltration.

Dosage recommendations for cidofovir are available for renally competent as well as impaired patients; however, there are no data for patients undergoing continuous renal replacement therapy. We determined the single-dose concentration-versus-time profile of cidofovir in a critically ill patient undergoing continuous venovenous hemofiltration (CVVH). One dose of 450 mg cidofovir (5 mg/kg) was administered intravenously due to a proven cytomegalovirus (CMV) infection and failure of first-line antiviral therapy. Additionally, 2 g of probenecid was administered orally 3 h prior to and 1 g was administered 2 h as well as 8 h after completion of the infusion. The concentrations of cidofovir in serum and ultrafiltrate were assessed by high-performance liquid chromatography. The peak serum concentration measured at 60 min postinfusion was 28.01 mg/liter at the arterial port. The trough serum level was 19.33 mg/liter at the arterial port after 24 h. The value of the area under the concentration-versus-time curve from 0 to 24 h was 543.8 mg·h/liter. The total body clearance was 2.46 ml/h/kg, and the elimination half-life time was 53.32 h. The sieving coefficient was 0.138±0.022. Total removal of the drug was 30.99% after 24 h. Because of these data, which give us a rough idea of the concentration profile of cidofovir in patients undergoing CVVH, a toxic accumulation of the drug following repeated doses may be expected. Further trials have to be done to determine the right dosage of cidofovir in patients undergoing CVVH to avoid toxic accumulation of the drug.

Pharmacokinetics of ganciclovir during continuous venovenous hemodiafiltration in critically ill patients.

Ganciclovir is an antiviral agent that is frequently used in critically ill patients with cytomegalovirus (CMV) infections. Continuous venovenous hemodiafiltration (CVVHDF) is a common extracorporeal renal replacement therapy in intensive care unit patients. The aim of this study was to investigate the pharmacokinetics of ganciclovir in anuric patients undergoing CVVHDF. Population pharmacokinetic analysis was performed for nine critically ill patients with proven or suspected CMV infection who were undergoing CVVHDF. All patients received a single dose of ganciclovir at 5 mg/kg of body weight intravenously. Serum and ultradiafiltrate concentrations were assessed by high-performance liquid chromatography, and these data were used for pharmacokinetic analysis. Mean peak and trough prefilter ganciclovir concentrations were 11.8 ± 3.5 mg/liter and 2.4 ± 0.7 mg/liter, respectively. The pharmacokinetic parameters elimination half-life (24.2 ± 7.6 h), volume of distribution (81.2 ± 38.3 liters), sieving coefficient (0.76 ± 0.1), total clearance (2.7 ± 1.2 liters/h), and clearance of CVVHDF (1.5 ± 0.2 liters/h) were determined. Based on population pharmacokinetic simulations with respect to a target area under the curve (AUC) of 50 mg · h/liter and a trough level of 2 mg/liter, a ganciclovir dose of 2.5 mg/kg once daily seems to be adequate for anuric critically ill patients during CVVHDF.

[Pharmaceutical care for a multimorbid patient mainly suffering from chronic obstructive pulmonary disease]. / Pharmazeutische Betreuung eines multimorbiden Patienten mit Schwerpunkt chronisch obstruktive Lungenerkrankung.

In multimorbid patients the medication for COPD is associated with a high risk for drug-drug interactions, medication errors and adverse drug events. This article describes how the drug therapy of a patient with COPD was optimized using SOAP notes.

BAY 1213790, a fully human IgG1 antibody targeting coagulation factor XIa: First evaluation of safety, pharmacodynamics, and pharmacokinetics.

BACKGROUND: Coagulation factor XI (FXI) contributes to the development of thrombosis but appears to play only a minor role in hemostasis and is therefore an attractive anticoagulant drug target. OBJECTIVES: To evaluate the safety, pharmacodynamic, and pharmacokinetic properties of BAY 1213790, a fully human immunoglobulin (Ig) G1 antibody targeting activated coagulation FXI (FXIa), in healthy men. METHODS: In this phase 1, single-blind, parallel-group, placebo-controlled, dose-escalation study, 83 healthy Caucasian men were randomized 4:1 to receive a single 60-minute intravenous infusion of BAY 1213790 (0.015-10 mg/kg) or placebo. Adverse events, pharmacodynamic parameters (including activated partial thromboplastin time [aPTT]) and pharmacokinetic parameters were determined. Volunteers were followed up for 150 days. RESULTS: BAY 1213790 demonstrated favorable safety and tolerability; there were no observed cases of bleeding or clinically relevant antidrug antibody formation. One volunteer (1.2%) experienced an infusion reaction. Following intravenous administration of BAY 1213790, dose-dependent increases in aPTT (maximal mean increase relative to baseline: 1.85 [conventional method] and 2.17 [kaolin-triggered method]) and rotational thromboelastometry whole blood clotting time were observed, as well as dose-dependent reductions in FXI activity. Bleeding times did not increase following administration of BAY 1213790 and were similar for all dose cohorts, including placebo. Measurable and dose-dependent increases in systemic exposure were detected for all doses of BAY 1213790 of 0.06 mg/kg or higher. CONCLUSIONS: Based on these safety, pharmacodynamic, and pharmacokinetic results, further evaluation of BAY 1213790 in patients with, or at risk of, thrombosis is warranted.

Prospective, Multicenter Study of 5-Fluorouracil Therapeutic Drug Monitoring in Metastatic Colorectal Cancer Treated in Routine Clinical Practice.

BACKGROUND: Studies have demonstrated that body surface area-based dosing of chemotherapy drugs leads to significant individual exposure variability, with a substantial risk of under- or overdosing. The present study was initiated to validate the use of therapeutic drug management (TDM) to personalize 5-fluorouracil (5-FU) dosing in patients with metastatic colorectal cancer treated in routine clinical practice. PATIENTS AND METHODS: A total of 75 patients with metastatic colorectal cancer from 8 German medical centers received ≤ 6 administrations of infusional 5-FU according to the AIO (folinate, 5-FU; n = 16), FOLFOX6 (leucovorin calcium [folinic acid], 5-FU, and oxaliplatin; n = 26), or FUFOX (oxaliplatin plus 5-FU/folinic acid; n = 33) regimen. Initial infusional 5-FU dosing for all patients was determined by the BSA. Individual 5-FU exposure (area under the curve [AUC]) was measured using an immunoassay of a blood sample taken during each infusion. To achieve a target AUC of 20 to 30 mg × h/L, subsequent infusional 5-FU doses were adjusted according to the previous cycle's 5-FU AUC. The primary objective was to confirm that TDM of infusional 5-FU resulted in an increased proportion of patients in the target AUC range at the fourth versus the first administration. The secondary objective was to determine whether 5-FU TDM reduced the treatment-related toxicities compared with the historical data. RESULTS: The average 5-FU AUC at the first administration was 18 ± 6 mg × h/L, with 64%, 33%, and 3% of the patients below, within, or above the target AUC range, respectively. By the fourth administration, the average 5-FU AUC was 25 ± 7 mg × h/L (P < .001), with 54% of patients within the target 5-FU AUC range (P = .0294). The incidence of 5-FU-related grade 3 and 4 diarrhea (4.6%), nausea (3.4%), fatigue (0.0%), and mucositis (0.2%) was reduced compared with the historical data, despite 55% of the patients receiving increased doses. CONCLUSION: Personalization of 5-FU dosing using TDM in routine clinical practice resulted in significantly improved 5-FU exposure and suggested a lower incidence of 5-FU-related toxicities.

Pharmacokinetically based dosing of weekly paclitaxel to reduce drug-related neurotoxicity based on a single sample strategy.

PURPOSE: The present simulation study was initiated to develop a limited sampling strategy and pharmacokinetically based dosing algorithm of weekly paclitaxel based on pharmacokinetic (PK) and chemotherapy-induced peripheral neuropathy (CIPN) data from a large database. METHODS: We used paclitaxel plasma concentrations from 200 patients with solid tumors receiving weekly paclitaxel infusions to build a population PK model and a proportional odds model on CIPN. Different limited sampling strategies were tested on their accuracy to estimate the individual paclitaxel time-above-threshold-concentration of 0.05 µmol/L (T c>0.05µM), which is a common threshold for paclitaxel. A dosing algorithm was developed based on the population distribution of paclitaxel T c>0.05µM and the correlation between paclitaxel T c>0.05µM and CIPN. A trial simulation based on paclitaxel PK and CIPN was performed using empirical Bayes estimations, applying the proposed dosing algorithm and a single 24-h paclitaxel PK sample. RESULTS: A single paclitaxel plasma concentration taken 18-30 h after the start of chemotherapy infusion adequately predicted T c>0.05µM. By using an empirical dosing algorithm to target an average paclitaxel T c>0.05µM between 10 and 14 h, Bayesian simulations of repetitive (adapted) dosing suggested a potential reduction of grade 2 CIPN from 9.6 to 4.4 %. CONCLUSIONS: This simulation study proposes a pharmacokinetically based dosing algorithm for weekly paclitaxel and shows potential improvement of the benefit/risk ratio by using empirical Bayesian models.

Evaluation of a pharmacology-driven dosing algorithm of 3-weekly paclitaxel using therapeutic drug monitoring: a pharmacokinetic-pharmacodynamic simulation study.

BACKGROUND AND OBJECTIVE: Severe neutropenia is the most frequent and important toxicity of 3-weekly paclitaxel and puts patients at substantial risk of infectious complications. It is well known that the time during which paclitaxel plasma concentrations exceed 0.05 µmol/L (T(C>0.05)) correlates with the extent of neutropenia. This study was initiated to develop a dosing algorithm that would be able to reduce severe neutropenia by targeting an individual paclitaxel T(C>0.05) between 26 and 31 hours, and could be validated in a prospective randomized trial by comparing it to conventional dosing of paclitaxel. METHODS: Paclitaxel plasma concentration-time (n = 273) and absolute neutrophil count (ANC) data (152 of the 273 patients) were pooled from two previous studies and submitted to population pharmacokinetic and pharmacodynamic modelling using nonlinear mixed-effects modelling software NONMEM® version VII. To fit the data, we used a previously described 3-compartment model with saturable elimination and distribution, coupled to a semiphysiological model with a linear function to describe the myelotoxic effect of paclitaxel (E(paclitaxel)) on circulating neutrophils (neutropenia). Patient age, sex, body surface area (BSA), bilirubin and renal function were tested as potential covariates on the maximum elimination capacity of paclitaxel (VM(EL)). Limited sampling strategies were tested on the pharmacokinetic model for their accuracy to predict paclitaxel T(C>0.05). Subsequently, we proposed a first-cycle dosing algorithm that accounted for BSA, patient age and sex, while later cycles accounted for the previous-cycle paclitaxel T(C>0.05) (target: 26 to 31 hours) and ANC nadir to adapt the paclitaxel dose for the next treatment cycle. To test the adequacy of the proposed dosing algorithm, we used extensive data simulations on the final pharmacokinetic/pharmacodynamic model, generating datasets of 1000 patients for six subsequent treatment cycles. Grade 4 neutropenia was tested as a potential endpoint for a prospective clinical trial and simulated for two scenarios, i.e. conventional dosing of paclitaxel 200 mg/m(2) every 3 weeks, and personalized, pharmacology-driven dosing as outlined above. RESULTS: Concentration-time data for paclitaxel were adequately described by the 3-compartment model. Also, individual ANC counts were adequately described by the semiphysiological model using a linear function to describe E(paclitaxel) on neutropenia. Patient age, sex, bilirubin and BSA were significant and independent covariates on the elimination of paclitaxel. Paclitaxel VM(EL) was 16% higher in males than in female patients, and a 10-year increase in age led to a 13% decrease in VM(EL). A single paclitaxel plasma concentration 24 hours after the start of infusion was adequate to predict paclitaxel T(C>0.05) (root squared mean error [RSME] = +0.5%), and the addition of an end-of-infusion sample did not further improve precision (RSME = -0.6%). Data simulations on the final pharmacokinetic/pharmacodynamic model and using the proposed dosing algorithm resulted in a first-cycle paclitaxel dose ranging from 150 to 185 mg/m(2) for women and from 165 to 200 mg/m(2) for men. Dose adaptations for cycles two to six ranged from -40% to +30%, with a final median paclitaxel dose of 167 mg/m(2) (range 76 to 311 mg/m(2)). When compared with conventional dosing (paclitaxel 200 mg/m(2) every 3 weeks), personalized dosing reduced grade 4 neutropenia in cycle one from 15% to 7%, and further to 4% in cycle 2. CONCLUSION: This study proposes a pharmacology-driven dosing algorithm of 3-weekly paclitaxel to reduce the incidence of grade 4 neutropenia. A randomized clinical trial comparing this dosing algorithm with conventional BSA-based dosing of paclitaxel in patients with advanced non-small cell lung cancer is currently ongoing.