Dataset Information

Retrospective Analysis Using Pharmacokinetic/Pharmacodynamic Modeling and Simulation Offers Improvements in Efficiency of the Design of Volunteer Infection Studies for Antimalarial Drug Development.

ABSTRACT: Volunteer infection studies using the induced blood stage malaria (IBSM) model have been shown to facilitate antimalarial drug development. Such studies have traditionally been undertaken in single-dose cohorts, as many as necessary to obtain the dose-response relationship. To enhance ethical and logistic aspects of such studies, and to reduce the number of cohorts needed to establish the dose-response relationship, we undertook a retrospective in silico analysis of previously accrued data to improve study design. A pharmacokinetic (PK)/pharmacodynamic (PD) model was developed from initial fictive-cohort data for OZ439 (mixing the data of the three single-dose cohorts as: n = 2 on 100 mg, 2 on 200 mg, and 4 on 500 mg). A three-compartment model described OZ439 PKs. Net growth of parasites was modeled using a Gompertz function and drug-induced parasite death using a Hill function. Parameter estimates for the PK and PD models were comparable for the multidose single-cohort vs. the pooled analysis of all cohorts. Simulations based on the multidose single-cohort design described the complete data from the original IBSM study. The novel design allows for the ascertainment of the PK/PD relationship early in the study, providing a basis for rational dose selection for subsequent cohorts and studies.

SUBMITTER: Andrews KA

PROVIDER: S-EPMC7993277 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:Dihydroartemisinin-piperaquine is a recommended first-line artemisinin combination therapy for Plasmodium falciparum malaria. Piperaquine is also under consideration for other antimalarial combination therapies. The aim of this study was to develop a pharmacokinetic-pharmacodynamic model that might be useful when optimizing the use of piperaquine in new antimalarial combination therapies. The pharmacokinetic-pharmacodynamic model was developed using data from a previously reported dose-ranging study where 24 healthy volunteers were inoculated with 1,800 blood-stage Plasmodium falciparum parasites. All volunteers received a single oral dose of piperaquine (960 mg, 640 mg, or 480 mg) on day 7 or day 8 after parasite inoculation in separate cohorts. Parasite densities were measured by quantitative PCR (qPCR), and piperaquine levels were measured in plasma samples. We used nonlinear mixed-effect modeling to characterize the pharmacokinetic properties of piperaquine and the parasite dynamics associated with piperaquine exposure. The pharmacokinetics of piperaquine was described by a three-compartment disposition model. A semimechanistic parasite dynamics model was developed to explain the maturation of parasites, sequestration of mature parasites, synchronicity of infections, and multiplication of parasites, as seen in natural clinical infections with P. falciparum malaria. Piperaquine-associated parasite killing was estimated using a maximum effect (Emax) function. Treatment simulations (i.e., 3-day oral dosing of dihydroartemisinin-piperaquine) indicated that to be able to combat multidrug-resistant infections, an ideal additional drug in a new antimalarial triple-combination therapy should have a parasite reduction ratio of ≥102 per life cycle (38.8 h) with a duration of action of ≥2 weeks. The semimechanistic pharmacokinetic-pharmacodynamic model described here offers the potential to be a valuable tool for assessing and optimizing current and new antimalarial drug combination therapies containing piperaquine and the impact of these therapies on killing multidrug-resistant infections. (This study has been registered in the Australian and New Zealand Clinical Trials Registry under no. ANZCTRN12613000565741.).

Project description:BackgroundOptimal dosing of propofol to maintain appropriate anesthetic depth is challenging in severely obese (SO) adolescents. We previously reported that total body weight (TBW) is predictive of propofol clearance. This study was aimed at characterizing pharmacokinetics (PK) and pharmacodynamics (PD) of propofol in SO adolescents, using bispectral index (BIS), and toward developing PK/PD model-based dosing guidelines.MethodsA prospective PK/PD study was conducted in 26 SO children and adolescents aged 9-18 years (body mass index 31-69 kg·m(-2)), undergoing surgery with intravenous propofol anesthesia clinically titrated by providers blinded to BIS. BIS data and propofol infusion schemes were recorded. Venous blood samples collected during and after propofol infusion were assayed for propofol concentrations. A propofol PK/PD model was developed using NONMEM and model-based simulations were performed to determine propofol dosing regimens targeting BIS of 50 ± 10.ResultsA three-compartment PK model linked to a sigmoidal inhibitory Emax PD model by a first-order rate constant, adequately described the propofol concentration (n = 375) and BIS (n = 3334) data. TBW was the most predictive covariate for propofol clearance [CL (l·min(-1) ) = 1.65 × (TBW/70)(0.75)]. An effect-site propofol concentration of 3.19 μg·ml(-1) was estimated for half-maximal effect, with no identifiable predictive covariates. The proposed maintenance dosing regimen targeted to a BIS of 50 ± 10, based on our PK/PD model, was able to predict desired propofol concentrations and BIS in a representative obese teen when used in conjunction with accepted PK/PD models for children/obese adults (PK:Eleveld/PD: Cortinez), further supporting evidence for the dosing based on TBW.ConclusionThis is the first study to describe the PK/PD of propofol in SO adolescents. The proposed maintenance dosing regimen for propofol uses TBW in an allometric function as a dosing scalar, with an exponent of 0.75. Our results suggest no relevant effect of obesity on the propofol concentration-BIS relationship.

Project description:Mechanism-based pharmacokinetic-pharmacodynamic (PK/PD) modelling is the standard computational technique for simulating drug treatment of infectious diseases with the potential to enhance our understanding of drug treatment outcomes, drug deployment strategies, and dosing regimens. Standard methodologies assume only a single drug is used, it acts only in its unconverted form, and that oral drugs are instantaneously absorbed across the gut wall to their site of action. For drugs with short half-lives, this absorption period accounts for a significant period of their time in the body. Treatment of infectious diseases often uses combination therapies, so we refined and substantially extended the PK/PD methodologies to incorporate (i) time lags and drug concentration profiles resulting from absorption across the gut wall and, if required, conversion to another active form; (ii) multiple drugs within a treatment combination; (iii) differing modes of action of drugs in the combination: additive, synergistic, antagonistic; (iv) drugs converted to an active metabolite with a similar mode of action. This methodology was applied to a case study of two first-line malaria treatments based on artemisinin combination therapies (ACTs, artemether-lumefantrine and artesunate-mefloquine) where the likelihood of increased artemisinin tolerance/resistance has led to speculation on their continued long-term effectiveness. We note previous estimates of artemisinin kill rate were underestimated by a factor of seven, both the unconverted and converted form of the artemisinins kill parasites and the extended PK/PD methodology produced results consistent with field observations. The simulations predict that a potentially rapid decline in ACT effectiveness is likely to occur as artemisinin resistance spreads, emphasising the importance of containing the spread of artemisinin resistance before it results in widespread drug failure. We found that PK/PD data is generally very poorly reported in the malaria literature, severely reducing its value for subsequent re-application, and we make specific recommendations to improve this situation.

Project description:BackgroundNasal glucagon (NG) 3 mg is approved in Japan to treat hypoglycemia in pediatric patients with diabetes, but an NG clinical study has not been performed in Japanese children because of practical and ethical concerns.ObjectiveThe aim of this study is to support the dose rationale for NG 3 mg in Japanese pediatric patients with diabetes using modeling and simulation.MethodsWe used a pharmacokinetic/pharmacodynamic bridging approach to extrapolate the available clinical data to Japanese pediatric patients. Population pharmacokinetic/pharmacodynamic modeling was performed using data from seven clinical studies, including five studies in non-Japanese adults, one study in Japanese adults, and one study in non-Japanese pediatric patients. Simulation was then used to estimate glucagon exposure and glucose response after NG 3-mg administration for three age categories of Japanese pediatric patients: 4 to < 8, 8 to < 12, and 12 to < 18 years. Treatment success was defined as an increase in blood glucose to ≥ 70 or ≥ 20 mg/dL from nadir within 30 min after administration of NG 3 mg. Safety was assessed in relation to the predicted maximum glucagon concentration of NG 3 mg using NG clinical trial data and published data on intravenous and intramuscular glucagon.ResultsThe data showed a rapid and robust glucose response following NG 3 mg in Japanese and non-Japanese adults and non-Japanese pediatric patients, with some differences in glucagon exposure observed across studies. The pharmacokinetic/pharmacodynamic model described the observed clinical data well, and simulations indicated that > 99% of hypoglycemic Japanese pediatric patients in all three age groups would achieve treatment success. Predicted glucose responses to NG 3 mg in Japanese pediatric patients were comparable to those of intramuscular glucagon. Maximum concentration was not associated with the occurrence and severity of common adverse events (nausea, vomiting, and headache) in NG clinical studies. Furthermore, the predicted maximum concentration in Japanese pediatric patients, despite being higher than the observed maximum concentration in NG clinical studies, was substantially lower than the observed maximum concentration of 1 mg of intravenous glucagon, without serious safety issues.ConclusionsThis analysis suggests NG 3 mg has robust efficacy without serious safety concerns in Japanese pediatric patients with diabetes.

Dataset Information

Retrospective Analysis Using Pharmacokinetic/Pharmacodynamic Modeling and Simulation Offers Improvements in Efficiency of the Design of Volunteer Infection Studies for Antimalarial Drug Development.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets