Introduction Pharmacists are poised to be the health care professionals best suited to provide medication‐related consults and services based on a patient's genetics. Despite its potential benefits, the implementation of pharmacogenetic (PGx) testing into primary clinical settings has been slow among medically underserved populations. To our knowledge, this is the first time that PGx‐driven recommendations have been incorporated into a Comprehensive Medication Management (CMM) service in a Hispanic population. Objectives The aim of this study is to evaluate the clinical utility of adding PGx guidance into pharmacist‐driven CMM. Methods This is a pre‐ and post‐interventional design study. Patients were recruited from a psychologist's clinic. A total of 24 patients had a face‐to‐face interview with a pharmacist to complete a CMM, Personal Medication Record, and Medication‐Related Action Plan (MAP) blind to PGx findings. Collected buccal DNA samples were genotyped using drug‐metabolizing enzymes and transporters (DMET) Plus Array. Results The pharmacist generated new MAPs for each patient based on PGx results. Genetic variants that could potentially affect the safety and effectiveness of at least one drug in the pharmacotherapy were identified in 96% of patients, for whom the pharmacist changed the initial recommendations. Polymorphisms in genes encoding for isoenzymes CYP2D6, CYP2C19, and CYP2C9 were identified in 83%, 52%, and 41% of patients, respectively. Pharmacists performing CMM identified 22 additional medication problems after PGx determinations. Moreover, they agreed with the clinical utility of PGx in the studied sample based on perceived value of adding PGx to traditional CMM and its utility in the decision‐making process of pharmacists. Conclusions The study confirmed the critical role to be played by pharmacists in facilitating the clinical usage of relevant genetic information to optimize drug therapy decisions as well as their involvement on many levels of these multidisciplinary implementation efforts, including championing and leading PGx‐guided CMM services.
Immunocompetent mice, Fc receptor γ-chain deficient mice (Fcer1g−/−), and molecular tools as F(ab′)2 bivalent fragments appear as the most suitable biological models to study the mechanisms of the action of anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (mAbs). In vivo experiments contrasting antitumor effects of whole Abs and their bivalent fragments commonly involve a previous comparative pharmacokinetics study. In this paper, pharmacokinetics and biodistribution of an anti-mouse EGFR Ab were assessed using immunocompetent mice. 125I-labeled 7A7 mAb holds an elimination half-life (t1/2β) of 23.1 h in C57BL/6 mice. Accumulation of mAb was found in liver, spleen, kidneys, and mostly in lungs. We used an ELISA method to determine the t1/2β of a 7A7 mAb using the same experimental setting. Results from this new analysis revealed a t1/2β of 23.9 h, supporting this method as a safer and easier system to evaluate pharmacokinetics parameters of mAbs targeting mouse EGFR. Using this system we also studied pharmacokinetics of 7A7 F(ab′)2 fragment. A tenfold difference between the mAb and fragment t1/2β was found. These data support the use of the 7A7 F(ab′)2 fragment in in vivo studies to explore the contribution of the EGFR signaling blockade and the Fc region to the antitumor effect of 7A7 mAb in this autologous scenario.
This study aimed (1) to develop a semimechanistic pharmacokinetic (PK) model for nimotuzumab in patients with advanced breast cancer and (2) to identify demographic, biochemical, and clinical predictive factors of the PK variability. Data from a phase 1 study were analyzed using the nonlinear mixed-effects approach (NONMEM). A target-mediated disposition model that included 2 open PK compartments, the monoclonal antibody (mAb)-target binding, and target and mAb-target complex turnovers best described the linear and nonlinear PK. Covariates had no influence on the PK parameters. The final parameter estimates were 19.93 L (steady-state volume), 0.0045-0.0172 L/h (range of total clearance values), 6.96 μg/mL (steady-state binding constant), 5.50 h(-1) (target degradation rate constant), 1.43 (μg/mL) · h(-1) (complex formation rate), and 0.148 h(-1) (complex internalization rate constant). The model described the effect of the mAb-target binding, and target and mAb-target complex turnovers on nimotuzumab PK. Simulations showed that doses above 200 mg maintained the 50% target occupancy during all of the treatment. This model can be very useful for knowing the dosing schedules required for efficacy and supports further investigation of the pharmacokinetic/pharmacodynamic relationships of nimotuzumab to improve its therapeutic use.
Autosomal dominant polycystic kidney disease (ADPKD) is a genetic disease characterized by an overexpression and mislocalization of epidermal growth factor receptor (EGFR) to the apical membranes of cystic epithelial cells. Nimotuzumab is a humanized antibody that recognizes an extracellular domain III of human EGFR. The aim of this study was to assess the pharmacokinetic behavior of nimotuzumab in patients with ADPKD given as a single dose. A phase I, single‐center, and noncontrolled open clinical study was conducted. Five patients were enrolled at each of the following fixed‐dose levels: 50, 100, 200, and 400 mg. Intravenous continuous infusions of nimotuzumab were administered every 14 days during a year, except the first administration, when blood samples were drawn during 28 days for pharmacokinetic assessments. Subjects were closely monitored during the trial and at completion of the administration of nimotuzumab, including the anti‐idiotypic response. For the first time, nimotuzumab was used for treating a nononcological disease. The administration of nimotuzumab showed dose‐dependent kinetics. Nimotuzumab does not develop anti‐idiotypic response against the murine portion present in the hypervariable region of the antibody present in the serum of the patients treated. No significant differences were found in the systemic clearance between the 100‐ and 400‐mg dose, which indicates that the optimal biological dose is in this range of dose.
Objectives The inter-individual variability of warfarin dosing has been linked to genetic polymorphisms. This study was aimed at performing genotype-driven pharmacokinetic (PK) simulations to predict warfarin levels in Puerto Ricans. Methods Analysis of each individual dataset was performed by one-compartmental modeling using WinNonlin®v6.4. The k e of warfarin given a cytochrome P450 2C9 (CYP2C9) genotype ranged from 0.0189 to 0.0075 h−1. K a and V d parameters were taken from literature. Data from 128 subjects were divided into two groups (i.e., wild-types and carriers) and statistical analyses of PK parameters were performed by unpaired t-tests. Results In the carrier group (n=64), 53 subjects were single-carriers and 11 double-carriers (i.e., *2/*2, *2/*3, *2/*5, *3/*5, and *3/*8). The mean peak concentration (Cmax) was higher for wild-type (0.36±0.12 vs. 0.32±0.14 mg/L). Likewise, the average clearance (CL) parameter was faster among non-carriers (0.22±0.03 vs. 0.17±0.05 L/h; p=0.0001), with also lower area under the curve (AUC) when compared to carriers (20.43±6.97 vs. 24.78±11.26 h mg/L; p=0.025). Statistical analysis revealed a significant difference between groups with regard to AUC and CL, but not for Cmax. This can be explained by the variation of k e across different genotypes. Conclusions The results provided useful information for warfarin dosing predictions that take into consideration important individual PK and genotyping data.
ObjectivesThe inter-individual variability of warfarin dosing has been linked to genetic polymorphisms. This study was aimed at performing genotype-driven pharmacokinetic (PK) simulations to predict warfarin levels in Puerto Ricans.MethodsAnalysis of each individual dataset was performed by one-compartmental modeling using WinNonlin®v6.4. The ke of warfarin given a cytochrome P450 2C9 (CYP2C9) genotype ranged from 0.0189 to 0.0075 h−1. Ka and Vd parameters were taken from literature. Data from 128 subjects were divided into two groups (i.e., wild-types and carriers) and statistical analyses of PK parameters were performed by unpaired t-tests.ResultsIn the carrier group (n=64), 53 subjects were single-carriers and 11 double-carriers (i.e., *2/*2, *2/*3, *2/*5, *3/*5, and *3/*8). The mean peak concentration (Cmax) was higher for wild-type (0.36±0.12 vs. 0.32±0.14 mg/L). Likewise, the average clearance (CL) parameter was faster among non-carriers (0.22±0.03 vs. 0.17±0.05 L/h; p=0.0001), with also lower area under the curve (AUC) when compared to carriers (20.43±6.97 vs. 24.78±11.26 h mg/L; p=0.025). Statistical analysis revealed a significant difference between groups with regard to AUC and CL, but not for Cmax. This can be explained by the variation of ke across different genotypes.ConclusionsThe results provided useful information for warfarin dosing predictions that take into consideration important individual PK and genotyping data.
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