scholarly journals Pharmacogenomics of methadone: a narrative review of the literature

2020 ◽  
Vol 21 (12) ◽  
pp. 871-887
Author(s):  
Senthil Packiasabapathy ◽  
Blessed W Aruldhas ◽  
Nicole Horn ◽  
Brian R Overholser ◽  
Sara K Quinney ◽  
...  
Keyword(s):  
Genetic Variants ◽  
Single Gene ◽  
Predictive Ability ◽  
Pharmacodynamic Modeling ◽  
Population Pharmacokinetic ◽  
Cytochrome P450 Enzymes ◽  
Duration Of Action ◽  
P Glycoprotein ◽  
Surgical Pain ◽  
Clinical Responses

Background: Methadone, a synthetic opioid with longer duration of action and lower abuse potential compared with morphine, is used to prevent opioid withdrawal, as well as to manage chronic and acute surgical pain. The variability in response to methadone has been widely recognized. The purpose of this article is to review the literature on the pharmacogenetic factors underlying this variability. Materials & methods: This is a narrative overview of the literature on the genetic variants affecting pharmacodynamics and pharmacokinetics of methadone, retrieved from searches of databases such as PubMed and google scholar. Discussion: Clinical responses to methadone may be affected by genetic variants in the opioidergic, dopaminergic and neurotrophic pathways. Polymorphisms in genes related to disposition and elimination of methadone alter the pharmacokinetics, and possibly pharmacodynamics of methadone. Cytochrome P450 enzymes and P-glycoprotein variants contribute to the interindividual variability in methadone pharmacokinetics. Evidence for single gene variants affecting methadone response remains weak. Multiple genetic variants must be considered in conjunction to improve predictive ability. Conclusion: Evidence remains scarce at this time, to recommend pharmacogenetic testing before methadone administration. Well-powered clinical studies are needed with population pharmacokinetic-pharmacodynamic modeling and multigenetic signature-based predictions to enable tailored use of methadone in clinical practice.

Pharmacokinetics and Pharmacodynamics of Cisatracurium in Young and Elderly Adult Patients

1996 ◽  
Vol 84 (5) ◽  
pp. 1083-1091 ◽  
Author(s):  
Shahpoor S. Sorooshian ◽  
Michael A. Stafford ◽  
Nigel B. Eastwood ◽  
Alastair H. Boyd ◽  
Christopher J. Hull ◽  
...  
Keyword(s):  
Muscle Relaxant ◽  
Time Course ◽  
Venous Blood ◽  
The Elderly ◽  
Adult Patients ◽  
Pharmacodynamic Modeling ◽  
Population Pharmacokinetic ◽  
Elderly Adult ◽  
Elderly Adults ◽  
Duration Of Action

Background The effects of a muscle relaxant may differ in elderly compared with young adult patients for a variety of reasons. The authors compared the effects of a new muscle relaxant (cisatracurium) in young and elderly adults and used pharmacokinetic/pharmacodynamic modeling to identify factors explaining differences in time course of effect. Methods Thirty-one young (18-50 yr) and 33 elderly ( > 65 yr) patients anesthetized with nitrous oxide, isoflurane, and fetanyl were studied. Cisatracurium (0.1 mg/kg) was given after induction of anesthesia and later additional boluses of 0.025 mg/kg or an infusion of cisatracurium was given. Neuromuscular transmission was measured using the first twitch of the train-of-four response at the adductor pollicis after supramaximal stimulation of the ulnar nerve at 2 Hz every 15 s. Five venous blood samples were obtained for plasma drug concentration at intervals ranging from 2 to 120 min from every patient. Three additional samples were obtained from those who received an infusion. A population pharmacokinetic/pharmacodynamic model was fitted to the plasma concentration and effect data. The parameters of the model were permitted to vary with age to identify where differences existed between young and elderly adults. Results Onset of block was delayed in the elderly; values being mean 3.0 (95% confidence interval 1.75-11.4) min and 4.0 (2.4-6.5) min in the young and elderly, respectively (P < 0.01). Duration of action was similar in the two groups. Plasma clearance was 319 (293-345) ml/min in the study population and did not differ between young and elderly patients. Apparent volume of distribution was 13.28 (9.9-16.7) 1 and 9.6 (7.6-11.7) 1 in the elderly and young adults, respectively (P < 0.05). There also were differences in pharmacodynamic parameters between the young and elderly; the predominant change being a slower rate of biophase equilibration (ke0) in the elderly (0.060 [0.052-0.068])/min compared with the young (0.071 [0.065-0.077]/min; P < 0.05). Conclusions The pharmacokinetics of cisatracurium differ only marginally between young and elderly adults. Onset is delayed in the elderly because of slower biophase equilibration.

Population pharmacokinetic and pharmacodynamic modeling of epinephrine administered using a mobile inhaler

2015 ◽  
Vol 30 (6) ◽  
pp. 391-399 ◽  
Author(s):  
Sebastian Frechen ◽  
Ahmed Abbas Suleiman ◽  
Ali Mohammad Nejad Sigaroudi ◽  
Bertil Wachall ◽  
Uwe Fuhr
Keyword(s):  
Pharmacodynamic Modeling ◽  
Population Pharmacokinetic

Population pharmacokinetic and pharmacodynamic modeling of capecitabine and its metabolites in breast cancer patients

2021 ◽  
Author(s):  
Nastja Lunar ◽  
Marie-Christine Etienne-Grimaldi ◽  
Pauline Macaire ◽  
Fabienne Thomas ◽  
Florence Dalenc ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
Pharmacodynamic Modeling ◽  
Population Pharmacokinetic ◽  
Breast Cancer Patients

Population pharmacokinetic-pharmacodynamic model of oxfendazole in healthy adults in a multiple ascending dose and food effect study and target attainment analysis

2021 ◽  
Author(s):  
Thanh Bach ◽  
Gregory A. Deye ◽  
Ellen E. Codd ◽  
John Horton ◽  
Patricia Winokur ◽  
...  
Keyword(s):  
Safety Concern ◽  
Hemoglobin Concentration ◽  
Healthy Adults ◽  
Pharmacodynamic Modeling ◽  
Parasitic Infections ◽  
Population Pharmacokinetic ◽  
Phase I Clinical Trials ◽  
Target Attainment ◽  
Indirect Response Model ◽  
Indirect Response

Oxfendazole is a potent veterinary antiparasitic drug undergoing development for human use to treat multiple parasitic infections. Results from two recently completed Phase I clinical trials conducted in healthy adults showed that the pharmacokinetics of oxfendazole is nonlinear, affected by food, and, after the administration of repeated doses, appeared to mildly affect hemoglobin concentrations. To facilitate oxfendazole dose optimization for its use in patient populations, the relationship among oxfendazole dose, pharmacokinetics and hemoglobin concentration was quantitatively characterized using population pharmacokinetic-pharmacodynamic modeling. In fasting subjects, oxfendazole pharmacokinetics was well described by a one-compartment model with first-order absorption and elimination. The change in oxfendazole pharmacokinetics when administered following a fatty meal was captured by an absorption model with one transit compartment and increased bioavailability. The effect of oxfendazole exposure on hemoglobin concentration in healthy adults was characterized by a lifespan indirect response model in which oxfendazole has positive but minor inhibitory effect on red blood cell synthesis. Further simulation indicated that oxfendazole has a low risk of posing a safety concern regarding hemoglobin concentration, even at a high oxfendazole dose of 60 mg/kg once daily. The final model was further used to perform comprehensive target attainment simulations for whipworm infection and filariasis at various dose regimens and target attainment criteria. The results of our modeling work, when adopted appropriately, have the potential to greatly facilitate oxfendazole dose regimen optimization in patient populations with different types of parasitic infections.

Optimizing Amikacin Dosage in Pediatrics Based on Population Pharmacokinetic/Pharmacodynamic Modeling

2018 ◽  
Vol 20 (3) ◽  
pp. 265-272 ◽  
Author(s):  
Saeed Alqahtani ◽  
Manal Abouelkheir ◽  
Abdullah Alsultan ◽  
Yasmine Elsharawy ◽  
Aljawharah Alkoraishi ◽  
...  
Keyword(s):  
Pharmacodynamic Modeling ◽  
Population Pharmacokinetic

Maxacalcitol Pharmacokinetic–Pharmacodynamic Modeling and Simulation for Secondary Hyperparathyroidism in Patients Receiving Maintenance Hemodialysis

Drug Research ◽  
2021 ◽  
Author(s):  
Mizuki Fukazawa-Shinotsuka ◽  
Tomohisa Saito ◽  
Masaichi Abe ◽  
Satofumi Iida ◽  
I-Ting Wang ◽  
...  
Keyword(s):  
Clinical Study ◽  
Modeling And Simulation ◽  
Secondary Hyperparathyroidism ◽  
Compartment Model ◽  
Japanese Patients ◽  
Pharmacodynamic Modeling ◽  
Maintenance Hemodialysis ◽  
Population Pharmacokinetic ◽  
Limit Of Quantification ◽  
Clinical Pharmacology Study

Abstract Background Maxacalcitol was approved in Taiwan in 2018 as the first active vitamin D3 injection for secondary hyperparathyroidism (SHPT) in patients on maintenance hemodialysis. However, no data from any clinical study with maxacalcitol in Taiwanese patients is available. Objectives This analysis aimed to evaluate the profiles of parathyroid hormone (PTH) and calcium (Ca) concentrations in Taiwanese SHPT patients on hemodialysis and maxacalcitol. Methods We developed population pharmacokinetic (PK) and pharmacodynamic (PD) models using a modeling and simulation approach. The data for these analyses were obtained from two studies: a clinical pharmacology study in Japanese patients and an ethnic comparison study in healthy Japanese and -Taiwanese volunteers. We then conducted a simulation study with a PK-PD model comprising the PK and PD models developed here. Results Serum maxacalcitol concentration profile was modeled using a two-compartment model that took into consideration the distribution of concentrations below the lower limit of quantification. An ethnic difference in clearance was included in the PK model as a covariate. A PD model that used a PTH/Ca feedback loop best described the observed data. There were no significant differences in Ca or PTH concentrations between Taiwanese and Japanese based on the simulation results from our PK-PD model, even though maxacalcitol exposure was approximately 40% higher in Taiwanese than in Japanese. Conclusions On the basis of these population PK and PD analyses and the clinical study conducted in Japan, there is no clinically relevant difference between Taiwanese and Japanese in terms of serum Ca or PTH levels.

Complex cardiovascular diseases: the genetics of arterial hypertension

ESC CardioMed ◽  
2018 ◽  
pp. 732-736
Author(s):  
Georg Ehret
Keyword(s):  
Blood Pressure ◽  
Arterial Hypertension ◽  
Genetic Variants ◽  
Single Gene ◽  
Primary Hypertension ◽  
Genetic Types ◽  
Risk Variants ◽  
Cardiovascular Risk Prediction ◽  
Single Gene Defect ◽  
Substantial Extent

Arterial hypertension appears as two genetic types: primary hypertension is to a substantial extent determined by a large number of genetic risk variants, whereas rare patients with a familial hypertensive syndrome have a single gene defect that drives the elevated blood pressure. The familial hypertensive syndromes have been instrumental in highlighting blood pressure-regulating pathways that almost exclusively cluster in the kidney and in the mineralocorticoid pathways. Conversely, hundreds or more genetic variants cause the genetic component of primary hypertension and each risk variant causes a small blood pressure increase. The blood vessels appear to be one tissue in which these variants principally act and surprisingly there is little overlap with pathways of kidney and hormone pathways. Genetic testing is useful for the rare familial hypertensive syndrome, but in primary hypertension cardiovascular risk prediction can currently not be improved by genotyping.

Population Pharmacokinetic and Pharmacodynamic Modeling in Beagle Dogs Sedated by Propofol Microemulsion

2006 ◽  
Vol 50 (6) ◽  
pp. 689
Author(s):  
Byung Moon Choi ◽  
Sung Moon Jung ◽  
Kyun Seop Bae ◽  
Gyu Jeong Noh
Keyword(s):  
Pharmacodynamic Modeling ◽  
Population Pharmacokinetic ◽  
Beagle Dogs
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