Pharmacokinetics in Optimizing Dosing

A special issue of Pharmaceutics (ISSN 1999-4923).

Deadline for manuscript submissions: closed (31 January 2020) | Viewed by 23344

Special Issue Editors


E-Mail Website
Guest Editor
Laboratory of Pharmacology, Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal
Interests: pharmacometrics; PK/PD models; therapeutic drug monitoring; personalized medicine; central drugs

E-Mail Website
Guest Editor
Laboratory of Pharmacology, Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal
Interests: personalized medicine; pharmacokinetics; therapeutic drug monitoring; antiepileptic drugs; antidepressant drugs; nose-to-brain delivery; ABC efflux transporters
Special Issues, Collections and Topics in MDPI journals

E-Mail Website
Guest Editor
CICS-UBI—Health Sciences Research Centre, University of Beira Interior, Av. Infante D. Henrique, 6200-506 Covilhã, Portugal
Interests: pharmacokinetics; ADME; bioavailability; drug evaluation; drug delivery; systemic drug exposure
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The selection of the most appropriate drug or combination of drugs as well as the identification of the treatment regimen that maximize drug efficacy and minimize drug toxicity are at the cornerstone of the success of pharmacotherapy. However, these are constantly clinical challenges not only because they must take into account not only the efficacy spectrum of the drug itself and potential drug-associated adverse events, but also additional factors that influence drugs pharmacokinetics, such as individual genetic variability, the presence of comorbidities, and potential drug-drug interactions that contribute to unpredictable fluctuations in drug plasma concentrations.

Therefore, therapeutic drug monitoring of plasma/serum concentration helps clinicians to identify individual therapeutic drug concentrations and characterize the individual pharmacokinetic profile of a drug, generating activity-over-time profiles that are adopted as the standard way of using pharmacokinetics to individualize treatment.

A pharmacokinetic/pharmacodynamic (PK/PD) directed approach for optimal dosing of several drugs in special populations (e.g. pediatrics, elderly, pregnancy, renal/hepatic failure) is progressively gaining a clinical foothold and has already resulted in significant dose adaptations of drugs including antiepileptics, anticoagulants, antibiotics and anti-tumoral drugs.

Prof. Dr. Amílcar Falcão
Prof. Dr. Ana Fortuna
Prof. Dr. Gilberto Alves
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Pharmaceutics is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Published Papers (6 papers)

Order results
Result details
Select all
Export citation of selected articles as:

Research

15 pages, 1532 KiB  
Article
Pharmacokinetic Monitoring of Levetiracetam in Portuguese Refractory Epileptic Patients: Effect of Gender, Weight and Concomitant Therapy
by Rui Silva, Anabela Almeida, Joana Bicker, Joana Gonçalves, Andreia Carona, Ana Silva, Isabel Santana, Francisco Sales, Amílcar Falcão and Ana Fortuna
Pharmaceutics 2020, 12(10), 943; https://doi.org/10.3390/pharmaceutics12100943 - 1 Oct 2020
Cited by 5 | Viewed by 2487
Abstract
Levetiracetam is a second-generation antiepileptic drug, widely used in the treatment of focal and generalized epilepsy due to its pharmacokinetic and safety profiles. Its pharmacokinetic monitoring is ascribed as useful to personalize its dosing regimen. The aim of the present study was to [...] Read more.
Levetiracetam is a second-generation antiepileptic drug, widely used in the treatment of focal and generalized epilepsy due to its pharmacokinetic and safety profiles. Its pharmacokinetic monitoring is ascribed as useful to personalize its dosing regimen. The aim of the present study was to describe, for the first time, the pharmacokinetics of levetiracetam in Portuguese refractory epileptic patients. Therefore, a retrospective study was carried out on 65 Portuguese refractory epileptic patients (pharmacokinetic study: 48; validation study: 17) admitted to the Refractory Epilepsy Centre of the Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal. The pharmacokinetic parameters of levetiracetam were estimated by applying a one-compartment model with first-order absorption and elimination analysis. Male patients showed higher distribution volume (Vd/F) and oral clearance (CL/F) than female patients (median Vd/F: 52.40 L in males and 38.60 L in females, p = 0.011; median CL/F: 4.71 L/h in males and 3.91 L/h in females, p = 0.028). Higher values of Vd/F (p = 0.026) and CL/F (p = 0.003) were also found in overweight patients relative to normal weight and obese patients. Carbamazepine was the co-administered antiepileptic drug that mostly affected the pharmacokinetics of levetiracetam, increasing both Vd/F (61.30 L with carbamazepine and 39.10 L without carbamazepine, p = 0.007) and CL/F (6.71 L/h with carbamazepine and 3.91 L/h without carbamazepine, p < 0.001). The pharmacokinetics of levetiracetam was affected by gender, body mass index, and co-administration of carbamazepine. This study highlights the impact of several factors on the CL/ and Vd/F of levetiracetam when administered to refractory epileptic patients. The importance of its pharmacokinetic monitoring in clinical pharmacy stands out, thereby enabling the optimization of antiepileptic drug therapy. Full article
(This article belongs to the Special Issue Pharmacokinetics in Optimizing Dosing)
Show Figures

Figure 1

13 pages, 2258 KiB  
Article
Real Life Population Pharmacokinetics Modelling of Eight Factors VIII in Patients with Severe Haemophilia A: Is It Always Relevant to Switch to an Extended Half-Life?
by Quentin Allard, Zoubir Djerada, Claire Pouplard, Yohann Repessé, Dominique Desprez, Hubert Galinat, Birgit Frotscher, Claire Berger, Annie Harroche, Anne Ryman, Claire Flaujac, Pierre Chamouni, Benoît Guillet, Fabienne Volot, Jean Szymezak, Philippe Nguyen and Yoann Cazaubon
Pharmaceutics 2020, 12(4), 380; https://doi.org/10.3390/pharmaceutics12040380 - 21 Apr 2020
Cited by 12 | Viewed by 3232
Abstract
We retrospectively analysed the data files of 171 adults and 87 children/adolescents with severe haemophilia, except for 14 patients (moderate; minor) (1), to develop a global population pharmacokinetic (PK) model for eight factors VIII (FVIII) that could estimate individual PK parameters for targeting [...] Read more.
We retrospectively analysed the data files of 171 adults and 87 children/adolescents with severe haemophilia, except for 14 patients (moderate; minor) (1), to develop a global population pharmacokinetic (PK) model for eight factors VIII (FVIII) that could estimate individual PK parameters for targeting the desired level of FVIII activity (FVIII:C); and (2) to compare half-life (HL) in patients switching from a standard half-life (SHL) to an extended half-life (EHL) and evaluate the relevance of the switch. One-stage clotting assay for the measurement of FVIII activity (FVIII:C, IU/mL) was used for population PK modelling. The software, Monolix version 2019R1, was used for non-linear mixed-effects modelling. A linear two-compartment model best described FVIII:C. The estimated PK parameters (between-subject variability) were: 2640 mL (23.2%) for volume of central compartment (V1), 339 mL (46.8%) for volume of peripheral compartment (V2), 135 mL/h for Q (fixed random effect), and 204 mL/h (34.9%) for clearance (Cl). Weight, age, and categorical covariate EHL were found to influence Cl and only weight for V1. This model can be used for all of the FVIII cited in the study. Moreover, we demonstrated, in accordance with previous studies, that Elocta had longer half-life (EHL) than SHL (mean ratio: 1.48) as compared to Advate, Factane, Kogenate, Novoeight, and Refacto. Full article
(This article belongs to the Special Issue Pharmacokinetics in Optimizing Dosing)
Show Figures

Graphical abstract

13 pages, 1540 KiB  
Article
Novel Population Pharmacokinetic Model for Linezolid in Critically Ill Patients and Evaluation of the Adequacy of the Current Dosing Recommendation
by Amaia Soraluce, Helena Barrasa, Eduardo Asín-Prieto, Jose Ángel Sánchez-Izquierdo, Javier Maynar, Arantxazu Isla and Alicia Rodríguez-Gascón
Pharmaceutics 2020, 12(1), 54; https://doi.org/10.3390/pharmaceutics12010054 - 9 Jan 2020
Cited by 23 | Viewed by 3495
Abstract
Antimicrobial treatment in critically ill patients remains challenging. The aim of this study was to develop a population pharmacokinetic model for linezolid in critically ill patients and to evaluate the adequacy of current dosing recommendation (600 mg/12 h). Forty inpatients were included, 23 [...] Read more.
Antimicrobial treatment in critically ill patients remains challenging. The aim of this study was to develop a population pharmacokinetic model for linezolid in critically ill patients and to evaluate the adequacy of current dosing recommendation (600 mg/12 h). Forty inpatients were included, 23 of whom were subjected to continuous renal replacement therapies (CRRT). Blood and effluent samples were drawn after linezolid administration at defined time points, and linezolid levels were measured. A population pharmacokinetic model was developed, using NONMEM 7.3. The percentage of patients that achieved the pharmacokinetic/pharmacodynamic (PK/PD) targets was calculated (AUC24/MIC > 80 and 100% T>MIC). A two-compartment model best described the pharmacokinetics of linezolid. Elimination was conditioned by the creatinine clearance and by the extra-corporeal clearance if the patient was subjected to CRRT. For most patients, the standard dose of linezolid did not cover infections caused by pathogens with MIC ≥ 2 mg/L. Continuous infusion may be an alternative, especially when renal function is preserved. Full article
(This article belongs to the Special Issue Pharmacokinetics in Optimizing Dosing)
Show Figures

Graphical abstract

20 pages, 2021 KiB  
Article
Development and Evaluation of Physiologically Based Pharmacokinetic Drug–Disease Models for Predicting Rifampicin Exposure in Tuberculosis and Cirrhosis Populations
by Muhammad F. Rasool, Sundus Khalid, Abdul Majeed, Hamid Saeed, Imran Imran, Mohamed Mohany, Salim S. Al-Rejaie and Faleh Alqahtani
Pharmaceutics 2019, 11(11), 578; https://doi.org/10.3390/pharmaceutics11110578 - 5 Nov 2019
Cited by 18 | Viewed by 5452
Abstract
The physiologically based pharmacokinetic (PBPK) approach facilitates the construction of novel drug–disease models by allowing incorporation of relevant pathophysiological changes. The aim of the present work was to explore and identify the differences in rifampicin pharmacokinetics (PK) after the application of its single [...] Read more.
The physiologically based pharmacokinetic (PBPK) approach facilitates the construction of novel drug–disease models by allowing incorporation of relevant pathophysiological changes. The aim of the present work was to explore and identify the differences in rifampicin pharmacokinetics (PK) after the application of its single dose in healthy and diseased populations by using PBPK drug–disease models. The Simcyp® simulator was used as a platform for modeling and simulation. The model development process was initiated by predicting rifampicin PK in healthy population after intravenous (i.v) and oral administration. Subsequent to successful evaluation in healthy population, the pathophysiological changes in tuberculosis and cirrhosis population were incorporated into the developed model for predicting rifampicin PK in these populations. The model evaluation was performed by using visual predictive checks and the comparison of mean observed/predicted ratios (ratio(Obs/pred)) of the PK parameters. The predicted PK parameters in the healthy population were in adequate harmony with the reported clinical data. The incorporation of pathophysiological changes in albumin concentration in the tuberculosis population revealed improved prediction of clearance. The developed PBPK drug–disease models have efficiently described rifampicin PK in tuberculosis and cirrhosis populations after administering single drug dose, as the ratio(Obs/pred) for all the PK parameters were within a two-fold error range. The mechanistic nature of the developed PBPK models may facilitate their extension to other diseases and drugs. Full article
(This article belongs to the Special Issue Pharmacokinetics in Optimizing Dosing)
Show Figures

Graphical abstract

16 pages, 2643 KiB  
Article
Population Pharmacokinetics Modelling and Simulation of Mitotane in Patients with Adrenocortical Carcinoma: An Individualized Dose Regimen to Target All Patients at Three Months?
by Yoann Cazaubon, Yohann Talineau, Catherine Feliu, Céline Konecki, Jennifer Russello, Olivier Mathieu and Zoubir Djerada
Pharmaceutics 2019, 11(11), 566; https://doi.org/10.3390/pharmaceutics11110566 - 31 Oct 2019
Cited by 15 | Viewed by 4139
Abstract
Mitotane is the most effective agent in post-operative treatment of adrenocortical carcinoma. In adults, the starting dose is 2–3 g/day and should be slightly increased to reach the therapeutic index of 14–20 mg/L. This study developed a population PK model for mitotane and [...] Read more.
Mitotane is the most effective agent in post-operative treatment of adrenocortical carcinoma. In adults, the starting dose is 2–3 g/day and should be slightly increased to reach the therapeutic index of 14–20 mg/L. This study developed a population PK model for mitotane and to simulate recommended/high dosing regimens. We retrospectively analyzed the data files of 38 patients with 503 plasma concentrations for the pharmacokinetic analysis. Monolix version 2019R1 was used for non-linear mixed-effects modelling. Monte Carlo simulations were performed to evaluate the probability of target attainment (PTA ≥ 14 mg/L) at one month and at three months. Mitotane concentration data were best described by a linear one-compartment model. The estimated PK parameters (between-subject variability) were: 8900 L (90.4%) for central volume of distribution (V) and 70 L·h−1 (29.3%) for clearance (Cl). HDL, Triglyceride (Tg) and a latent covariate were found to influence Cl. The PTA at three months for 3, 6, 9, and 12 g per day was 10%, 55%, 76%, and 85%, respectively. For a loading dose of 15 g/day for one month then 5 g/day, the PTA in the first and third months was 57 and 69%, respectively. This is the first PKpop model of mitotane highlighting the effect of HDL and Tg covariates on the clearance as well as a subpopulation of ultrafast metabolizer. The simulations suggest that recommended dose regimens are not enough to target the therapeutic threshold in the third month. Full article
(This article belongs to the Special Issue Pharmacokinetics in Optimizing Dosing)
Show Figures

Graphical abstract

12 pages, 1477 KiB  
Communication
Intracellular PD Modelling (PDi) for the Prediction of Clinical Activity of Increased Rifampicin Dosing
by Ghaith Aljayyoussi, Samantha Donnellan, Stephen A. Ward and Giancarlo A. Biagini
Pharmaceutics 2019, 11(6), 278; https://doi.org/10.3390/pharmaceutics11060278 - 13 Jun 2019
Cited by 2 | Viewed by 3840
Abstract
Increasing rifampicin (RIF) dosages could significantly reduce tuberculosis (TB) treatment durations. Understanding the pharmacokinetic-pharmacodynamics (PK–PD) of increasing RIF dosages could inform clinical regimen selection. We used intracellular PD modelling (PDi) to predict clinical outcomes, primarily time to culture conversion, of [...] Read more.
Increasing rifampicin (RIF) dosages could significantly reduce tuberculosis (TB) treatment durations. Understanding the pharmacokinetic-pharmacodynamics (PK–PD) of increasing RIF dosages could inform clinical regimen selection. We used intracellular PD modelling (PDi) to predict clinical outcomes, primarily time to culture conversion, of increasing RIF dosages. PDi modelling utilizes in vitro-derived measurements of intracellular (macrophage) and extracellular Mycobacterium tuberculosis sterilization rates to predict the clinical outcomes of RIF at increasing doses. We evaluated PDi simulations against recent clinical data from a high dose (35 mg/kg per day) RIF phase II clinical trial. PDi-based simulations closely predicted the observed time-to-patient culture conversion status at eight weeks (hazard ratio: 2.04 (predicted) vs. 2.06 (observed)) for high dose RIF-based treatments. However, PDi modelling was less predictive of culture conversion status at 26 weeks for high-dosage RIF (99% predicted vs. 81% observed). PDi-based simulations indicate that increasing RIF beyond 35 mg/kg/day is unlikely to significantly improve culture conversion rates, however, improvements to other clinical outcomes (e.g., relapse rates) cannot be ruled out. This study supports the value of translational PDi-based modelling in predicting culture conversion rates for antitubercular therapies and highlights the potential value of this platform for the improved design of future clinical trials. Full article
(This article belongs to the Special Issue Pharmacokinetics in Optimizing Dosing)
Show Figures

Graphical abstract

Back to TopTop