Population Pharmacokinetic-pharmacodynamic Analysis Research Articles

Population Pharmacokinetic-Pharmacodynamic Analysis of a Reserpine-Induced Myalgia Model in Rats.

(1) Background: Fibromyalgia syndrome (FMS) is a chronic pain condition with widespread pain and multiple comorbidities, for which conventional therapies offer limited benefits. The reserpine-induced myalgia (RIM) model is an efficient animal model of FMS in rodents. This study aimed to develop a pharmacokinetic-pharmacodynamic (PK-PD) model of reserpine in rats, linking to its impact on monoamines (MAs). (2) Methods: Reserpine was administered daily for three consecutive days at dose levels of 0.1, 0.5, and 1 mg/kg. A total of 120 rats were included, and 120 PK and 828 PD observations were collected from 48 to 96 h after the first dose of reserpine. Non-linear mixed-effect data analysis was applied for structural PK-PD model definition, variability characterization, and covariate analysis. (3) Results: A one-compartment model best described reserpine in rats (V = 1.3 mL/kg and CL = 4.5 × 10-1 mL/h/kg). A precursor-pool PK-PD model (kin = 6.1 × 10-3 mg/h, kp = 8.6 × 10-4 h-1 and kout = 2.7 × 10-2 h-1) with a parallel transit chain (k0 = 1.9 × 10-1 h-1) characterized the longitudinal levels of MA in the prefrontal cortex, spinal cord, and amygdala in rats. Reserpine stimulates the degradation of MA from the pool compartment (Slope1 = 1.1 × 10-1 h) and the elimination of MA (Slope2 = 1.25 h) through the transit chain. Regarding the reference dose (1 mg/kg) of the RIM model, the administration of 4 mg/kg would lead to a mean reduction of 65% (Cmax), 80% (Cmin), and 70% (AUC) of MA across the brain regions tested. (4) Conclusions: Regional brain variations in neurotransmitter depletion were identified, particularly in the amygdala, offering insights for therapeutic strategies and biomarker identification in FMS research.

Neurocognitive effect of biased µ-opioid receptor agonist oliceridine, a utility function analysis and comparison with morphine.

Oliceridine (Olinvyk®) is a μ-opioid receptor agonist that in contrast to conventional opioids preferentially engages the G-protein-coupled signaling pathway. We determined the utility function of oliceridine versus morphine based on neurocognitive tests and cold pressor test. The study had a randomized, double-blind, placebo-controlled, partial block 3-way crossover design. Experiments were performed in 20 male and female volunteers. Subjects received intravenous oliceridine (1 or 3 mg; cohorts of 10 subjects/dose), morphine (5 or 10 mg; cohorts of 10 subjects/dose) or placebo on three separate occasions. Prior to and following dosing, neurocognitive tests, cold pressor test and plasma drug concentrations were obtained at regular intervals. Population pharmacokinetic-pharmacodynamic analyses served as basis for construction of a utility function, which is an objective function of probability of benefit minus probability of harm. Antinociception served as measure of benefit, slowing of saccadic peak velocity and increased body sway as measures of neurocognitive harm. The oliceridine and morphine C50's, i.e. the effect-site concentrations causing 50% effect, were: antinociception 13±2 and 23±7 ng/mL, saccadic peak velocity 90±14 and 54±15 ng/mL, and body sway 10±2 and 5.6±0.8 ng/mL, respectively. The ratio oliceridine/morphine of the therapeutic indices, C50(benefit)/C50(harm), were 0.34 (95% CI 0.17-0.7; p<0.01) for saccadic peak velocity and 0.33 (0.16-0.50; p<0.01) for body sway. The oliceridine utility was positive across the effect-site concentration 5-77 ng/mL, indicative of a greater probability of benefit than harm. The morphine utility was not significantly different from zero from 0-100 ng/mL. Over the concentration range 15-50 ng/mL the oliceridine utility was superior to that of morphine (p < 0.01). Similar observations were made for body sway. These data indicate that over the clinical concentration range, oliceridine is an analgesic with a favorable safety profile over morphine when considering analgesia and neurocognitive function.

Safety, Pharmacokinetics, and Exposure-Response Modeling of Nedosiran in Participants With Severe Chronic Kidney Disease.

Nedosiran is an investigational RNA-interference therapeutic in development for primary hyperoxaluria (PH). Because nedosiran undergoes renal clearance, we assessed its pharmacokinetic profile in non-PH participants with normal kidney function and Stages 4/5 chronic kidney disease (CKD), the latter with/without dialysis. Nedosiran exposure-response modeling in patients with PH Subtype 1 (PH1) with different renal function level was performed to recommend a nedosiran dose for this subpatient population. In this open-label, single-dose, Phase 1 study, 24 participants with estimated glomerular filtration rate <30mL/min/1.73m2 (CKD Stages 4/5; on hemodialysis [Groups 1a, 1b] and not on hemodialysis [Group 2]) and 10participants with normal kidney function (estimated glomerular filtration rate ≥90mL/min/1.73m2 ; Group 3) received a single dose of subcutaneous nedosiran sodium 170mg. Group 1a received nedosiran 8hours before beginning hemodialysis, Group 1b received nedosiran 2hours after completing hemodialysis; Group 2 was not on hemodialysis. Nedosiran population pharmacokinetic-pharmacodynamic analyses were conducted using pooled data from this study and 4 others. Nedosiran pharmacokinetic exposure in non-PH participants with CKD Stages 4/5 was approximately 2-fold higher versus participants with normal kidney function. Hemodialysis timing relative to nedosiran administration had no clinically significant impact on pharmacokinetics (Group 1a vs 1b). Nedosiran was well tolerated. Modeling indicated that in patients with PH1 with CKD Stages 4/5, lower nedosiran doses provide similar exposure and potential reduction in 24-hour urinary oxalate to standard nedosiran doses in patients with PH1 with normal kidney function or CKD Stages 2/3. Nedosiran dosage reductions are recommended in patients with PH1 with CKD Stages 4/5; further adjustments are unnecessary if dialysis is started.

Expression of Concern: Impact of the Superoxide Dismutase 2 Val16Ala Polymorphism on the Relationship between Valproic Acid Exposure and Elevation of γ-Glutamyltransferase in Patients with Epilepsy: A Population Pharmacokinetic-Pharmacodynamic Analysis.

Expression of Concern: Impact of the Superoxide Dismutase 2 Val16Ala Polymorphism on the Relationship between Valproic Acid Exposure and Elevation of γ-Glutamyltransferase in Patients with Epilepsy: A Population Pharmacokinetic-Pharmacodynamic Analysis.

Developmental Population Pharmacokinetics-Pharmacodynamics of Meropenem in Chinese Neonates and Young Infants: Dosing Recommendations for Late-Onset Sepsis.

The pharmacokinetic (PK) studies of meropenem in Chinese newborns with late-onset sepsis (LOS) are still lacking. Causative pathogens of LOS and their susceptibility patterns in China differ from the data abroad. We, therefore, conducted a developmental population pharmacokinetic−pharmacodynamic analysis in Chinese newborns with the goal to optimize meropenem dosing regimens for LOS therapy. An opportunistic sampling strategy was used to collect meropenem samples, followed by model building and validation. A Monte Carlo simulation was performed to show the probability of target attainment (PTA) for various dosages. The information from 78 newborns (postmenstrual age: 27.4−46.1 weeks) was compiled and had a good fit to a 1-compartment model that had first order elimination. The median (range) values of estimated weight−normalized volume of distribution (V)and clearance (CL) were 0.60 (0.51−0.69) L/kg and 0.16 (0.04−0.51) L/h/kg, respectively. Covariate analysis revealed that postnatal age (PNA), gestational age (GA) and current weight (CW) were the most important factors in describing meropenem PK. Simulation results showed for LOS with a minimal inhibitory concentration (MIC) of 8 mg/L, the doses of 30 mg/kg 3 times daily (TID) as a 1-h infusion for newborns with GA ≤ 37 weeks and 40 mg/kg TID as a 3-h infusion for those with GA > 37 weeks were optimal, with PTA of 71.71% and 75.08%, respectively. In conclusion, we proposed an evidence-based dosing regimen of meropenem for LOS in Chinese newborns by using the population pharmacokinetic−pharmacodynamic analysis, based on domestic common pathogens and their susceptibility patterns.

Population pharmacokinetic and pharmacodynamic analysis of rivaroxaban in Chinese patients with non-valvular atrial fibrillation.

Rivaroxaban, a direct factor Xa inhibitor, is widely used for stroke prevention in patients with non-valvular atrial fibrillation (NVAF). The aim of this study was to conduct a population pharmacokinetic-pharmacodynamic (PK-PD) analysis of rivaroxaban in Chinese patients with NVAF to assess ethnic differences and provide model-based precision dosing. A total of 256 rivaroxaban plasma concentrations and 244 prothrombin time (PT) measurements were obtained from 195 Chinese NVAF patients from a prospective clinical trial. The population PK-PD model was developed using nonlinear mixed effects modeling (NONMEM) software. The PK of rivaroxaban was adequately described using a one-compartment model with first-order adsorption and elimination. Estimated glomerular filtration rate (eGFR) was identified as a major covariate for apparent clearance. No single nucleotide polymorphism was identified as a significant covariate. PT exhibited a linear relationship with rivaroxaban concentration. Total bilirubin (TBIL) and eGFR were identified as significant covariates for baseline PT. According to the Monte Carlo simulation, 15 mg for Chinese patients with eGFR ≥50 mL/min and normal liver function yielded an exposure comparable to 20 mg for Caucasian patients. Patients with moderately impaired renal function may require a lower dose of rivaroxaban to avoid overexposure. Moreover, there was an approximate 26% increase in PT levels in patients with TBIL of 34 μmol/L and eGFR of 30 mL/min, which could increase the risk of major bleeding. The established population PK-PD model could inform individualized dosing for Chinese NVAF patients who are administered rivaroxaban.

Ketamine Psychedelic and Antinociceptive Effects Are Connected.

Ketamine produces potent analgesia combined with psychedelic effects. It has been suggested that these two effects are associated and possibly that analgesia is generated by ketamine-induced dissociation. The authors performed a post hoc analysis of previously published data to quantify the pharmacodynamic properties of ketamine-induced antinociception and psychedelic symptoms. The hypothesis was that ketamine pharmacodynamics (i.e., concentration-effect relationship as well as effect onset and offset times) are not different for these two endpoints. Seventeen healthy male volunteers received escalating doses of S- and racemic ketamine on separate occasions. Before, during, and after ketamine infusion, changes in external perception were measured together with pain pressure threshold. A population pharmacokinetic-pharmacodynamic analysis was performed that took S- and R-ketamine and S- and R-norketamine plasma concentrations into account. The pharmacodynamics of S-ketamine did not differ for antinociception and external perception with potency parameter (median [95% CI]) C50, 0.51 (0.38 to 0.66) nmol/ml; blood-effect site equilibration half-life, 8.3 [5.1 to 13.0] min), irrespective of administration form (racemic ketamine or S-ketamine). R-ketamine did not contribute to either endpoint. For both endpoints, S-norketamine had a small antagonistic effect. The authors conclude that their data support an association or connectivity between ketamine analgesia and dissociation. Given the intricacies of the study related to the pain model, measurement of dissociation, and complex modeling of the combination of ketamine and norketamine, it is the opinion of the authors that further studies are needed to detect functional connectivity between brain areas that produce the different ketamine effects.

Abstract 1368: Population pharmacokinetic-pharmacodynamic analysis of KHK2455 in patients with locally advanced or metastatic solid tumors

Abstract BACKGROUND: KHK2455 is an oral selective inhibitor of Indoleamine 2,3-dioxygenase 1 (IDO1) and is being developed as an active immunotherapy to treat advanced or metastatic solid tumors. IDO1 is a rate-limiting enzyme that converts tryptophan (TRP) to kynurenine (KYN) and is linked to immunosuppression. IDO1 inhibition results in immune modulatory effects which may be important in boosting anti-cancer immune responses. The goal of this analysis was to develop a population pharmacokinetics (PK)-pharmacodynamics (PD) model to characterize KHK2455 exposure and its relationship to response in patients with locally advanced or metastatic solid tumors. METHOD: Plasma KHK2455 concentration, plasma KYN and TRP concentration were obtained from 36 subjects with locally advanced or metastatic solid tumors who received KHK2455 at 0.3, 1, 3, 10, 30, or 100 mg QD as a monotherapy run-in followed by combination therapy with anti-CCR4 antibody mogamulizumab in this first in human study of KHK2455. The nonlinear mixed effects modeling approach was used to develop a population PK-PD model using the data from both mono- and combination-therapy. The ratio of KYN to TRP (K:T ratio) was used as a PD marker. RESULTS: The population PK model included one-compartment model with transit compartment absorption, enterohepatic cycling, and linear elimination. The K:T ratio was well described by an indirect response model. Steady state simulations showed that, when compared to baseline, the K:T ratio decreased with increasing KHK2455 dose and reached to a constant nadir at 100 mg dose. CONCLUSIONS: A population PK-PD model was established to characterize the KHK2455 exposure and its relationship to response in patients with locally advanced or metastatic solid tumors. The PK-PD model will enable dose optimization simulations for the planned studies. ACKNOWLEDGEMENTS: We would like to express special appreciation to Dr. Solmaz Sahebjam, MD, for help in publishing this abstract. Citation Format: Krina Mehta, Shoko Koshiba, Maki Hasegawa, Tomonori Tayama, Douglas Marsteller, Floyd Fox, Yi Liu, Sergey Efuni, Denis Healy, Matthew Hruska. Population pharmacokinetic-pharmacodynamic analysis of KHK2455 in patients with locally advanced or metastatic solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1368.

Population pharmacokinetics-pharmacodynamics of ceftazidime in neonates and young infants: Dosing optimization for neonatal sepsis

Ceftazidime is a third-generation cephalosporin with high activity against many pathogens. But the ambiguity and diversity of the dosing regimens in neonates and young infants impair access to effective treatment. Thus, we conducted a population pharmacokinetic study of ceftazidime in this vulnerable population and recommended a model-based dosage regimen to optimize sepsis therapy. Totally 146 neonates and young infants (gestational age (GA): 36–43.4 weeks, postnatal age (PNA): 1–81 days, current weight (CW): 900–4500 g) were enrolled based on inclusion and exclusion criteria. Ceftazidime bloods samples (203) were obtained using the opportunistic sampling strategy and determined by the high-performance liquid chromatography. The population pharmacokinetic-pharmacodynamic analysis was conducted by nonlinear mixed effects model (NONMEM). A one-compartment model with first-order elimination best described the pharmacokinetic data. Covariate analysis showed the significance of GA, PNA, and CW on developmental pharmacokinetics. Monte Carlo simulation was performed based on above covariates and minimum inhibitory concentration (MIC). In the newborns with PNA ≤ 3 days (MIC=8 mg/L), the dose regimen was 25 mg/kg twice daily (BID). For the newborns with PNA > 3 days (MIC=16 mg/L), the optimal dose was 30 mg/kg three times daily (TID) for those with GA ≤ 37 weeks and 40 mg/kg TID for those with GA > 37 weeks. Overall, on the basis of the developmental population pharmacokinetic-pharmacodynamic analysis covering the whole range of neonates and young infants, the evidence-based ceftazidime dosage regimens were proposed to optimize neonatal early-onset and late-onset sepsis therapy.

Optimization of Micafungin Dosage for Chinese Patients with Sepsis in the Intensive Care Unit Based on a Population Pharmacokinetic-Pharmacodynamic Analysis.

This study aimed to identify parameters that influence micafungin pharmacokinetics in Chinese patients with sepsis in the intensive care unit and optimize micafungin dosage by determining the probability of reaching pharmacodynamic targets. Blood samples were collected from 32 Chinese patients with sepsis who were treated with micafungin. The samples were analyzed and used to build a population pharmacokinetic model. Monte Carlo simulations were performed to estimate the probability of achieving adequate plasma levels of micafungin against Candida species. Alanine aminotransferase and sequential organ failure assessment score were found to significantly influence the clearance and peripheral distribution volume of micafungin, respectively. Monte Carlo simulations based on area under the plasma concentration-time curve over 24h showed that patients must be administered at least 200 and 250mg micafungin daily to reach minimum inhibitory concentration breakpoints of 0.032 and 0.064mg/L for Candida glabrata and Candida tropicalis, respectively. Additionally, a probability of target attainment of ≥ 90% could not be achieved for Candida krusei or Candida parapsilosis with a 300mg daily dose. The recommended daily dose of micafungin (100mg) may produce low clinical success ratios in non-Candida albicans infections; therefore, higher doses should be administered to improve clinical outcomes.

Optimal Dosing of Ceftriaxone in Infants Based on a Developmental Population Pharmacokinetic-Pharmacodynamic Analysis.

Ceftriaxone is a third-generation cephalosporin used to treat infants with community-acquired pneumonia. Currently, there is a large variability in the amount of ceftriaxone used for this purpose in this particular age group, and an evidence-based optimal dose is still unavailable. Therefore, we investigated the population pharmacokinetics of ceftriaxone in infants and performed a developmental pharmacokinetic-pharmacodynamic analysis to determine the optimal dose of ceftriaxone for the treatment of infants with community-acquired pneumonia. A prospective, open-label pharmacokinetic study of ceftriaxone was conducted in infants (between 1 month and 2 years of age), adopting an opportunistic sampling strategy to collect blood samples and applying high-performance liquid chromatography to quantify ceftriaxone concentrations. Developmental population pharmacokinetic-pharmacodynamic analysis was conducted using nonlinear mixed effects modeling (NONMEM) software. Sixty-six infants were included, and 169 samples were available for pharmacokinetic analysis. A one-compartment model with first-order elimination matched the data best. Covariate analysis elucidated that age and weight significantly affected ceftriaxone pharmacokinetics. According to the results of a Monte Carlo simulation, with a pharmacokinetic-pharmacodynamic target of a free drug concentration above the MIC during 70% of the dosing interval (70% fT>MIC), regimens of 20 mg/kg of body weight twice daily for infants under 1 year of age and 30 mg/kg twice daily for those older than 1 year of age were suggested. The population pharmacokinetics of ceftriaxone were established in infants, and evidence-based dosing regimens for community-acquired pneumonia were suggested based on developmental pharmacokinetics-pharmacodynamics.

Developmental population pharmacokinetics-pharmacodynamics and dosing optimization of cefoperazone in children.

To evaluate the population pharmacokinetics of cefoperazone in children and establish an evidence-based dosing regimen using a developmental pharmacokinetic-pharmacodynamic approach in order to optimize cefoperazone treatment. A model-based, open-label, opportunistic-sampling pharmacokinetic study was conducted in China. Blood samples from 99 cefoperazone-treated children were collected and quantified by HPLC/MS. NONMEM software was used for population pharmacokinetic-pharmacodynamic analysis. This study was registered at ClinicalTrials.gov (NCT03113344). A two-compartment model with first-order elimination agreed well with the experimental data. Covariate analysis showed that current body weight had a significant effect on the pharmacokinetics of cefoperazone. Monte Carlo simulation showed that for bacteria for which cefoperazone has an MIC of 0.5 mg/L, 78.1% of hypothetical children treated with '40 mg/kg/day, q8h, IV drip 3 h' would reach the pharmacodynamic target. For bacteria for which cefoperazone has an MIC of 8 mg/L, 88.4% of hypothetical children treated with 80 mg/kg/day (continuous infusion) would reach the treatment goal. A 160 mg/kg/day (continuous infusion) regimen can cover bacteria for which cefoperazone has an MIC of 16 mg/L. Nevertheless, even if using the maximum reported dose of 160 mg/kg/day (continuous infusion), the ratio of hypothetical children reaching the treatment target was only 9.9% for bacteria for which cefoperazone has an MIC of 32 mg/L. For cefoperazone, population pharmacokinetics were evaluated in children and an appropriate dosing regimen was developed based on developmental pharmacokinetics-pharmacodynamics. The dose indicated in the instructions (20-160 mg/kg/day) can basically cover the clinically common bacteria for which cefoperazone has an MIC of ≤16 mg/L. However, for bacteria for which the MIC is >16 mg/L, cefoperazone is not a preferred choice.

Esketamine counters opioid-induced respiratory depression

BackgroundOpioids can produce life-threatening respiratory depression. This study tested whether subanaesthetic doses of esketamine stimulate breathing in an established human model of opioid-induced respiratory depression. MethodsIn a study with a randomised, double blind, placebo controlled, crossover design, 12 healthy, young volunteers of either sex received a dose escalating infusion of esketamine (cumulative dose 40 mg infused in 1 h) on top of remifentanil-induced respiratory depression. A population pharmacokinetic-pharmacodynamic analysis was performed with sites of drug action at baseline ventilation, ventilatory CO2-chemosensitivity, or both. ResultsRemifentanil reduced isohypercapnic ventilation (end-tidal PCO2 6.5 kPa) by approximately 40% (from 20 to 12 litre min−1) in esketamine and placebo arms of the study, through an effect on baseline ventilation and ventilatory CO2 sensitivity. The reduction in ventilation was related to a remifentanil effect on ventilatory CO2 sensitivity (~39%) and on baseline ventilation (~61%). Esketamine increased breathing through an exclusive stimulatory effect on ventilatory CO2 sensitivity. The remifentanil concentration that reduced ventilatory CO2 sensitivity by 50% (C50) was doubled at an esketamine concentration of 127 (84-191) ng ml−1 [median (interquartile range)]; the esketamine effect was rapid and driven by plasma pharmacokinetics. Placebo had no systematic effect on opioid-induced respiratory depression. ConclusionsEsketamine effectively countered remifentanil-induced respiratory depression, an effect that was attributed to an increase in remifentanil-reduced ventilatory CO2 chemosensitivity.

Population Pharmacokinetic–Pharmacodynamic Analysis to Compare the Effect of Moxifloxacin on QT Interval Prolongation Between Healthy Korean and Japanese Subjects

PurposeThe goal of this study was to evaluate the moxifloxacin-induced QT interval prolongation in healthy male and female Korean and Japanese volunteers to investigate interethnic differences. MethodsThis multicenter, randomized, double-blind, placebo-controlled, 2-way crossover study was conducted in healthy male and female Korean and Japanese volunteers. In each period, a single dose of moxifloxacin or placebo 400 mg was administered orally under fasting conditions. Triplicate 12-lead ECGs were recorded at defined time points before, up to 24 hours after dosing, and at corresponding time points during baseline. Serial blood sampling was conducted for pharmacokinetic analysis of moxifloxacin. The pharmacokinetic–pharmacodynamic data between the 2 ethnic groups were compared by using a typical analysis based on the intersection-union test and a nonlinear mixed effects method. FindingsA total of 39 healthy subjects (Korean, male: 10, female: 10; Japanese, male: 10, female: 9) were included in the analysis. The concentration–effect analysis revealed that there was no change in slope (and confirmed that the difference was caused by a change in the pharmacokinetic model of moxifloxacin). A 2-compartment model with first-order absorption provided the best description of moxifloxacin’s pharmacokinetic parameters. Weight and sex were selected as significant covariates for central volume of distribution and intercompartmental clearance, respectively. An Emax model (E[C]=[Emax⋅C]/[EC50+C]) described the QT interval data of this study well. However, ethnicity was not found to be a significant factor in a pharmacokinetic–pharmacodynamic link model. ImplicationsThe drug-induced QTc prolongations evaluated using moxifloxacin as the probe did not seem to be significantly different between these Korean and Japanese subjects. ClinicalTrials.gov identifier: NCT01876316.

Inter-study variability of preclinical in vivo safety studies and translational exposure-QTc relationships--a PKPD meta-analysis.

Preclinical cardiovascular safety studies (CVS) have been compared between facilities with respect to their sensitivity to detect drug-induced QTc prolongation (ΔQTc). Little is known about the consistency of quantitative ΔQTc predictions that are relevant for translation to humans. We derived typical ΔQTc predictions at therapeutic exposure (ΔQTcTHER ) with 95% confidence intervals (95%CI) for 3 Kv 11.1 (hERG) channel blockers (moxifloxacin, dofetilide and sotalol) from a total of 14 CVS with variable designs in the conscious dog. Population pharmacokinetic-pharmacodynamic (PKPD) analysis of each study was followed by a meta-analysis (pooling 2-6 studies including 10-32 dogs per compound) to derive meta-predictions of typical ΔQTcTHER . Meta-predictions were used as a reference to evaluate the consistency of study predictions and to relate results to those found in the clinical literature. The 95%CIs of study-predicted ΔQTcTHER comprised in 13 out of 14 cases the meta-prediction. Overall inter-study variability (mean deviation from meta-prediction at upper level of therapeutic exposure) was 30% (range: 1-69%). Meta-ΔQTcTHER predictions for moxifloxacin, dofetilide and sotalol overlapped with reported clinical QTc prolongation when expressed as %-prolongation from baseline. Consistent exposure-ΔQTc predictions were obtained from single preclinical dog studies of highly variable designs by systematic PKPD analysis, which is suitable for translational purposes. The good preclinical-clinical pharmacodynamic correlations obtained suggest that such an analysis should be more routinely applied to increase the informative and predictive value of results obtained from animal experiments.

Reversal of opioid-induced respiratory depression by BK-channel blocker GAL021: A pharmacokinetic-pharmacodynamic modeling study in healthy volunteers.

Opioid-induced respiratory depression (OIRD) is a serious and potentially life-threatening complication of opioid overdose, abuse, and misuse. An option to avert OIRD is to treat patients on strong opioids with respiratory stimulants that do not interact with the opioid system and consequently do not compromise opioid analgesic efficacy. The BK-channel blocker GAL021 is a respiratory stimulant acting at K(+) -channels expressed on type 1 carotid body cells. The authors performed a population pharmacokinetic-pharmacodynamic (PKPD) analysis on the ability of GAL021 to reverse alfentanil-induced respiratory depression in 12 male volunteers using an isohypercapnic experimental design. The analysis showed that (1) GAL021 interacts in a multiplicative fashion with alfentanil and GAL021, which predicts that GAL021 efficacy is reduced at low ventilation levels; (2) GAL021 has a rapid onset/offset with a blood-effect site equilibration half-life not different from zero; and (3) GAL021 displays ceiling in its efficacy to reverse OIRD.

Modeling the anesthetic effect of ropivacaine after a femoral nerve block in orthopedic patients: a population pharmacokinetic-pharmacodynamic analysis.

Even though ropivacaine is frequently used during orthopedic surgery, the relationship between plasma concentrations and degree of sensory anesthesia after a peripheral nerve block is currently unknown. The aim of this study was to characterize this relation using population pharmacokinetic-pharmacodynamic modeling. Femoral nerve block was performed by the anterior approach using a single injection (20 ml) of 0.5% ropivacaine hydrochloride in 20 patients scheduled for total knee arthroplasty under spinal anesthesia. Sensory thresholds in response to a gradual increase in transcutaneous electrical stimulation (primary endpoints), loss and recovery of ice-cold sensation, as well as total ropivacaine plasma concentrations were determined up to 4 days after administration of the local anesthetic. Using NONMEM (ICON, USA), sensory block was modeled by assuming an equilibration delay (ke0) between amount in the depot and effect-site compartments. Mean effect-site amount producing 90% of the maximum possible effect (AE90) was estimated as 20.2 mg. At 2 × AE90, the sigmoid Emax model predicted a mean onset time of 23.4 min and mean duration of 22.9 h. Interindividual variability (IIV) for AE50 was 49%. Typical ke0 half-life was 34.7 min (IIV = 52%) and steepness parameter 8.7 (IIV = 48%). None of the pharmacodynamic model parameters showed sex, age, or body weight dependency. A population pharmacokinetic/pharmacodynamic model was developed that quantitatively describes the sensory component of a femoral nerve block in orthopedic patients. Further clinical studies will be needed to validate the clinical relevance of this finding.

Impact of the superoxide dismutase 2 Val16Ala polymorphism on the relationship between valproic acid exposure and elevation of γ-glutamyltransferase in patients with epilepsy: a population pharmacokinetic-pharmacodynamic analysis.

BackgroundThere has been accumulating evidence that there are associations among γ-glutamyltransferase (γ-GT) elevation and all-cause mortality, cardiovascular diseases and metabolic diseases, including nonalcoholic fatty liver disease. The primary objective of this study was to evaluate the impact of the most common and potentially functional polymorphisms of antioxidant enzyme genes, i.e. superoxide dismutase 2 (SOD2), glutathione S-transferase M1 and glutathione S-transferase T1, on the γ-GT elevation during valproic acid (VPA) therapy.Methods and FindingsThis retrospective study included 237 and 169 VPA-treated Japanese patients with epilepsy for population pharmacokinetic and pharmacokinetic-pharmacodynamic analyses, respectively. A nonlinear mixed-effect model represented the pharmacokinetics of VPA and the relationships between VPA exposure and γ-GT elevation. A one-compartment model of the pharmacokinetic parameters of VPA adequately described the data; while the model for the probability of the γ-GT elevation was fitted using a logistic regression model, in which the logit function of the probability was a linear function of VPA exposure. The SOD2 Val16Ala polymorphism and complication with intellectual disability were found to be significant covariates influencing the intercept of the logit function for the probability of an elevated γ-GT level. The predicted mean percentages of the subjects with γ-GT elevation were about 2- to 3-fold, 3- to 4-fold and 4- to 8-fold greater in patients with the SOD2 Val/Val genotype but without any intellectual disability, those with the SOD2 Val/Ala or Ala/Ala genotype and intellectual disability and those with the SOD2 Val/Val genotype and intellectual disability, respectively, compared to those with the SOD2 Val/Ala or Ala/Ala genotype without intellectual disability.ConclusionOur results showed that the SOD2 Val16Ala polymorphism has an impact on the relationship between VPA exposure and γ-GT elevation in patients with epilepsy. These results suggest that determining the SOD2 genotype could be helpful for preventing the VPA-induced γ-GT elevation.

Determinants of the over-anticoagulation response during warfarin initiation therapy in Asian patients based on population pharmacokinetic-pharmacodynamic analyses.

To clarify pharmacokinetic-pharmacodynamic (PK-PD) factors associated with the over-anticoagulation response in Asians during warfarin induction therapy, population PK-PD analyses were conducted in an attempt to predict the time-courses of the plasma S-warfarin concentration, Cp(S), and coagulation and anti-coagulation (INR) responses. In 99 Chinese patients we analyzed the relationships between dose and Cp(S) to estimate the clearance of S-warfarin, CL(S), and that between Cp(S) and the normal prothrombin concentration (NPT) as a coagulation marker for estimation of IC50. We also analyzed the non-linear relationship between NPT inhibition and the increase in INR to derive the non-linear index λ. Population analyses accurately predicted the time-courses of Cp(S), NPT and INR. Multivariate analysis showed that CYP2C9*3 mutation and body surface area were predictors of CL(S), that VKORC1 and CYP4F2 polymorphisms were predictors of IC50, and that baseline NPT was a predictor of λ. CL(S) and λ were significantly lower in patients with INR≥4 than in those with INR<4 (190 mL/h vs 265 mL/h, P<0.01 and 3.2 vs 3.7, P<0.01, respectively). Finally, logistic regression analysis revealed that CL(S), ALT and hypertension contributed significantly to INR≥4. All these results indicate that factors associated with the reduced metabolic activity of warfarin represented by CL(S), might be critical determinants of the over-anticoagulation response during warfarin initiation in Asians.Trial RegistrationClinicalTrials.gov NCT02065388

Concentration-response Model of Lopinavir/Ritonavir in HIV-1–infected Pediatric Patients

The aims of this study were to analyze the viral load and CD4+ lymphocyte outcomes and the concentration-response of lopinavir/ritonavir (LPV/r) in the treatment of HIV-1-infected antiretroviral-naive children, to determine whether current dosing guidelines for LPV/r achieve Ctrough above 1.0 mg/L for naive patients to compare efficacy of World Health Organization 2010 and Food and Drug Administration dosing recommendations. Clinical and biologic examinations were performed before treatment, 1 month, 3 months and then every 3 months in 47 antiretroviral-naive children who started an LPV/r-based regimen. LPV concentrations were also monitored on a routine basis, after 2 weeks of treatment initiation, between 1 and 24 hours after dosing in all children. A population pharmacokinetic-pharmacodynamic analysis was performed using an HIV dynamic model. Simulations of World Health Organization 2010 and Food and Drug Administration dosing recommendations were compared in terms of viral suppression. The HIV dynamic model adequately described the data. According to the concentration-effect curve, the LPV concentration providing 90% (CLPV90) and 95% (CLPV95) of effect were 1.2 and 2.4 mg/L, respectively. The World Health Organization 2010 guidelines should provide a higher probability of viral success, particularly in infants. The CLPV90 derived from this model supports current dosing guidelines. However, the target of 2.4 mg/L corresponding to CLPV95 could be used to enhance the efficacy of this drug in treatment-naive children.