Full Pharmacokinetic Profiles Research Articles

Limited sampling strategy and population pharmacokinetic model of mycophenolic acid in pediatric patients with systemic lupus erythematosus: application of a double gamma absorption model with SAEM algorithm.

Mycophenolic acid (MPA), the active metabolite of mycophenolate mofetil (MMF), is widely used in the treatment of systemic lupus erythematosus (SLE). It has been shown that its therapeutic drug monitoring based on the area under the curve (AUC) improves treatment efficacy. MPA exhibits a complex bimodal absorption, and a double gamma distribution model has been already proposed in the past to accurately describe this phenomenon. These previous population pharmacokinetics models (POPPK) have been developed using iterative two stage Bayesian (IT2B) or non-parametric adaptive grid (NPAG) methods. However, non-linear mixed effect (NLME) approaches based on stochastic approximation expectation-maximization (SAEM) algorithms have never been published so far for this particular model. The objectives of this study were (i) to implement the double absorption gamma model in Monolix, (ii) to compare different absorption models to describe the pharmacokinetics of MMF, and (iii) to develop a limited sampling strategy (LSS) to estimate AUC in pediatric SLE patients. A data splitting of full pharmacokinetic profiles sampled in 67 children extracted either from the expert system ISBA (n = 34) or the hospital Saint Louis (n = 33) was performed into train (75%) and test (25%) sets. A POPPK was developed for MPA in the train set using a NLME and the SAEM algorithm and different absorption models were implemented and compared (first order, transit, or simple and double gamma). The best limited sampling strategy was then determined in the test set using a maximum-a-posteriori Bayesian method to estimate individual PK parameters and AUC based on three blood samples compared to the reference AUC calculated using the trapezoidal rule applied on all samples and performances were assessed in the test set. Mean patient age and dose was 13years old (5-18) and 18.1mg/kg (7.9-47.6), respectively. MPA concentrations (764) from 107 occasions were included in the analysis. A double gamma absorption with a first-order elimination from the central compartment best fitted the data. The optimal LSS with samples at 30min, 2h, and 3h post-dose exhibited good performances in the test set (mean bias - 0.32% and RMSE 21.0%). The POPPK developed in this study adequately estimated the MPA AUC in pediatric patients with SLE based on three samples. The double absorption gamma model developed with the SAEM algorithm showed very accurate fit and reduced computation time.

Comparison of pharmacokinetic study profiles of insulin in rat plasma through conventional sampling and microsampling by micro-LC-MS/MS.

Aim: With microsamples of blood, full pharmacokinetic profiles from individual animals can be obtained as an alternative to the sparse-sampling approach, where conventional volume samples from several animals are required. However, microsamples require assays that are more sensitive. Methods: The sensitivity of the LC-MS assay was increased 47-fold using microflow LC-MS. Results & conclusion: By analyzing both microsamples and conventional samples from the same animals, it is demonstrated that sparse-sampling profiles can be nonrepresentative of the full profiles. This bias can affect the tested treatment by increasing or reducing its apparent effect. Microsampling enables unbiased results compared with sparse-sampling. An increase in assay sensitivity to balance the low sample volumes was achievable by microflow LC-MS.

Application of machine learning to predict tacrolimus exposure in liver and kidney transplant patients given the MeltDose formulation

Machine Learning (ML) algorithms represent an interesting alternative to maximum a posteriori Bayesian estimators (MAP-BE) for tacrolimus AUC estimation, but it is not known if training an ML model using a lower number of full pharmacokinetic (PK) profiles (= "true" reference AUC) provides better performances than using a larger dataset of less accurate AUC estimates. The objectives of this study were: to develop and benchmark ML algorithms trained using full PK profiles to estimate MeltDose®-tacrolimus individual AUCs using 2 or 3 blood concentrations; and to compare their performance to MAP-BE. Data from liver (n = 113) and kidney (n = 97) transplant recipients involved in MeltDose-tacrolimus PK studies were used for the training and evaluation of ML algorithms. "True" AUC0-24h was calculated for each patient using the trapezoidal rule on the full PK profile. ML algorithms were trained to estimate tacrolimus true AUC using 2 or 3 blood concentrations. Performances were evaluated in 2 external sets of 16 (renal) and 48 (liver) transplant patients. Best estimation performances were obtained with the MARS algorithm and the following limited sampling strategies (LSS): predose (0), 8, and 12h post-dose (rMPE = - 1.28%, rRMSE = 7.57%), or 0 and 12h (rMPE = - 1.9%, rRMSE = 10.06%). In the external dataset, the performances of the final ML algorithms based on two samples in kidney (rMPE = - 3.1%, rRMSE = 11.1%) or liver transplant recipients (rMPE = - 3.4%, rRMSE = 9.86%) were as good as or better than those of MAP-BEs based on three time points. The MARS ML models developed using "true" MeltDose®-tacrolimus AUCs yielded accurate individual estimations using only two blood concentrations.

Development of an LC/MS/MS Method for Simultaneous Detection of 11 Polyphenols in Rat Plasma and Its Pharmacokinetic Application after Oral Administration of Coreopsis tinctoria Extract.

Eleven polyphenols, classified as flavonoid glycosides, flavonoid aglycones, and phenolic acids, are important bioactive components in the capitula of Coreopsis tinctoria (CCT). Nevertheless, their full pharmacokinetic profiles have not been demonstrated simultaneously. Therefore, a liquid chromatography - tandem mass spectrometry (LC/MS/MS) method was developed in the present work and used it to study the pharmacokinetics of these 11 compounds. We performed LC/MS/MS with a gradient mobile phase composed of water containing 0.1 % formic acid and acetonitrile containing 0.1 % formic acid on a Proshell 120 SB C18 column (2.1 mm×100 mm, 2.7 μm). We achieved a good chromatographic peak shape, resolution, and mass signal response, and multiple reaction monitoring facilitated the simultaneous detection of 11 analytes. In addition, we validated the selectivity, correlation coefficient, precision, extraction recovery, matrix effects, and stability of the LC/MS/MS method to be acceptable for 11 analytes in rat plasma. Subsequently, rats were orally administered with 50 % ethanol eluent of CCT (ECCT). Nine of 11 polyphenols were absorbed quickly (except for QCD and TCA), and their plasma levels peaked within 40 min. The exposure and Cmax values of flavonoid glycosides and phenolic acids were lower than those of flavonoid aglycones. This is the first report to demonstrate the pharmacokinetics of 11 polyphenols in ECCT, which may play an important role in future studies of the bioactive components of ECCT and their bioactive mechanisms.

In-depth investigation of the Silymarin effect on the pharmacokinetic parameters of sofosbuvir, GS-331007 and ledipasvir in rat plasma using LC-MS.

The use of complementary medicine (CMD) for liver support in Hepatitis C virus (HCV) patients sometimes coincides with the administration of oral antiviral drugs to eradicate the virus. This calls for a deep investigation of CMD effects on the pharmacokinetic parameters of these drugs to ensure their safety and efficacy. Silymarin (SLY), as a CMD, was selected to be given orally to healthy male rats with sofosbuvir (SFB) and ledipasvir (LED), a common regimen in HCV treatment. A new and sensitive LC-MS method was validated for the bioassay of SLY, LED, SFB and its inactive metabolite, GS-331007, in spiked plasma with lower limits of quantitation of 10, 1, 4 and 10 ng/ml, respectively. Moreover, the method was further applied to conduct a full pharmacokinetic profile of SFB, GS-331007 and ledipasvir with and without SLY. It was found that co-administration of SLY may expose the patient to unplanned high serum concentrations of SFB and LED. This could be accompanied by a decrease in SFB efficacy, potentially leading to therapeutic failure and the emergence of viral resistance.

Machine learning algorithms to estimate everolimus exposure trained on simulated and patient pharmacokinetic profiles.

Everolimus is an immunosuppressant with a small therapeutic index and large between‐patient variability. The area under the concentration versus time curve (AUC) is the best marker of exposure but measuring it requires collecting many blood samples. The objective of this study was to train machine learning (ML) algorithms using pharmacokinetic (PK) profiles from kidney transplant recipients, simulated profiles, or both types, and compare their performance for everolimus AUC0‐12h estimation using a limited number of predictors, as compared to an independent set of full PK profiles from patients, as well as to the corresponding maximum a posteriori Bayesian estimates (MAP‐BE). XGBoost was first trained on 508 patient interdose AUCs estimated using MAP‐BE, and then on 500–10,000 rich interdose PK profiles simulated using previously published population PK parameters. The predictors used were: predose, ~1 h, and ~2 h whole blood concentrations, differences between these concentrations, relative deviations from theoretical sampling times, morning dose, patient age, and time elapsed since transplantation. The best results were obtained with XGBoost trained on 5016 simulated profiles. AUC estimation achieved in an external dataset of 114 full‐PK profiles was excellent (root mean squared error [RMSE] = 10.8 μg*h/L) and slightly better than MAP‐BE (RMSE = 11.9 μg*h/L). Using more profiles (n = 10,035) did not improve the ML algorithm performance. The contribution of mixing patient and simulated profiles was significant only when they were in balanced numbers, with ~500 for each (RMSE = 12.5 μg*h/L), compared with patient data alone (RMSE = 18.0 μg*h/L).

Efficacy and safety of Mydriatic Microdrops for Retinopathy Of Prematurity Screening (MyMiROPS): study protocol for a non-inferiority crossover randomized controlled trial

BackgroundRetinopathy of prematurity (ROP) eye examination screening presupposes adequate mydriasis for an informative fundoscopy of preterm infants at risk, on a weekly basis. Systemic absorption of the instilled mydriatic regimens has been associated with various adverse events in this fragile population. This report aims to present the fully developed protocol of a full-scale trial for testing the hypothesis that the reduced mydriatic drop volume achieves adequate mydriasis while minimizing systemic adverse events.MethodsA non-inferiority crossover randomized controlled trial will be performed to study the efficacy and safety of combined phenylephrine 1.67% and tropicamide 0.33% microdrops compared with standard drops in a total of 93 preterm infants requiring ROP screening. Primary outcome will be the pupil diameter at 45 (T45) min after instillation. Pupil diameter at T90 and T120 will constitute secondary efficacy endpoints. Mixed-effects linear regression models will be developed, and the 95% confidence interval approach will be used for assessing non-inferiority. Whole blood samples will be analyzed using hydrophilic liquid chromatography–tandem mass spectrometry method (HILIC–MS/MS), for gathering pharmacokinetic (PK) data on the instilled phenylephrine, at nine specific time points within 3 h from mydriasis. Pooled PK data will be used due to ethical restrictions on having a full PK profile per infant. Heart rate, oxygen saturation, blood pressure measurements, and 48-h adverse events will also be recorded.DiscussionThis protocol is designed for a study powered to assess non-inferiority of microdrops compared with standard dilating drops. If our hypothesis is confirmed, microdrops may become a useful tool in ROP screening.Trial registrationClinicalTrials.govNCT05043077. Registered on 2 September 2021

Abstract OT2-20-01: Rogaratinib, palbociclib and fulvestrant in advanced hormone receptor-positive (HR+), FGFR1/2-positive breast cancer: Phase I trial plus an expansion cohort

Abstract Background: Novel therapies are needed upon progression to first-line CDK4/6 inhibitor (CDKi) plus endocrine therapy in advanced HR+ breast cancer. One frequent alteration driving resistance to CDKi plus hormones is FGFR1/2 amplification/overexpression. We have demonstrated that a combined assay of RNAScope and FISH, detecting RNA overexpression and genomic amplification of FGFR1/2, captures more FGFR-aberrant cases than either test alone. When these alterations exist, the triple estrogen receptor (ER), CDK4/6 and FGFR1/2 blockade is able to revert acquired resistance to CDKi (Breast Cancer Res; 23:21-37; 2021). Rogaratinib is a selective FGFR1-4 kinase inhibitor with significant activity in FGFR-aberrant malignancies. In this trial we will test the safety of the triple blockade combining fulvestrant, palbociclib and rogaratinib. We will also study its role as a resistant-reversion combo for FGFR1/2-positive, HR+ patients progressing to a CDK4/6 inhibitor plus aromatase inhibitor (AI) in the first-line metastatic setting. Trial design: Single-arm, prospective, multicentric, open-label, phase I dose-escalation trial. Patients will be pre-screened for amplification and/or overexpression of FGFR1/2 by FISH and RNAScope, during their first-line treatment. Positive patients will start treatment: on day 1, patients will receive rogaratinib q12 hours. On day 2, patients will continue on rogaratinib, receive fulvestrant (500 ug IM) and start on palbociclib (100 mg/day on days 1-21). A second fulvestrant dose (500 ug) will be administered in day +15. The first cycle will be 29 days, followed by 28-day cycles (continuous rogaratinib q12 hours days 1-28, fulvestrant 500 ug day 1, and palbociclib 100 mg/day days 1-21). Rogaratinib will be escalated, starting on 400 mg/bid in 200 mg/bid increments, following a classic 3+3 schedule. Patients experiencing ≤ grade 1 tolerable side effects as the greatest toxicity will be allowed to escalate palbociclib to 125 in cycle 2. A full pharmacokinetic profile and pharmacodynamics (plasma FGF23 and phosphate levels) will be performed on days 1 and 15 of cycle 1. The impact of the triple combination in immunodynamics will be assessed on PBMCs on days 2 and 15. Ten additional HR+, FGFR1/2 + patients will be accrued at the RP2D in an expansion cohort to study efficacy. RECIST 1.1 and NCI CTC AE V 5.0 criteria will be used for assessing disease control (q8 weeks) and toxicity. Eligibility criteria: Pre-screening: Women >18 year old diagnosed with advanced, non-curable HR+ breast cancer; 2) who are receiving first-line treatment with an AI and any oral CDKi; 3) Adequate organ function. Full screening: 4) Positivity for amplification (FISH ratio>2.2) and/or overexpression (RNAScope score of 3+ or 4+) of either FGFR1/2. 5) PD to first-line AI + CDKi within the last 28 days. 6) Recovery from previous toxicity to < tolerable G2. Specific aims: Primary: 1) To determine RP2D of the triple combination of fulvestrant, palbociclib and rogaratinib. 2) To assess the safety and toxicity of the former combination 3) To study the pharmacokinetics, pharmacodynamics and immunodynamics of the triplet. Secondary: 1) To determine the PFS time and 6-month PFS rate of the triplet in FGFR1/2 amplified/overexpressed patients AI + CDKi doublet. Statistical methods: We will follow a 3+3 escalation schedule; thus, the minimum and maximum number of patients for the dose-escalation phase will range between 6 and 18 (no escalation planned beyond 800 mg/bid rogaratinib). Ten additional patients will be accrued in the expansion cohort (N=28). The anticipated rate of positive screening is 40%; thus, we will screen approximately 70 patients. . Present accrual/target accrual: 55/70 screened; 16 FGFR1/2-positive (of 28 planned); 2 accrued and treated. Citation Format: Sonia Pernas, Cristina Hernando, Begoña Bermejo, Noelia Martinez-Jañez, Jose A García Saenz, Serafin Morales, Luis Manso, Jorge Silva, Juan A Guerra, Diego Malon, Silvana Mouron, Eduardo Caleiras, Miguel Quintela-Fandino. Rogaratinib, palbociclib and fulvestrant in advanced hormone receptor-positive (HR+), FGFR1/2-positive breast cancer: Phase I trial plus an expansion cohort [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT2-20-01.

Effects of Repeated Oral Administration of Esaxerenone on the Pharmacokinetics of Midazolam in Healthy Japanese Males

Background and ObjectiveEsaxerenone showed the potential to inhibit and induce activity against cytochrome P450 (CYP) 3A in in vitro studies. We investigated whether repeated administration of 5 mg/day esaxerenone for 14 days influences the pharmacokinetics of midazolam, a sensitive CYP3A substrate, in healthy Japanese males.MethodsThis single-centre, open-label, single-sequence study had two administration periods: period 1: single oral dose of 2 mg midazolam (day 0); period 2: repeated oral doses of 5 mg/day esaxerenone for 14 days, with a single oral dose of 2 mg midazolam on day 14. Full pharmacokinetic profiles of midazolam and 1-hydroxymidazolam on days 0 and 14 and safety data were obtained. Primary pharmacokinetic endpoints for midazolam were area under the plasma concentration-time curve (AUC) from zero to time of the last measurable concentration (AUClast), AUC from zero to infinity (AUCinf), and peak plasma concentration (Cmax).ResultsThe study included 28 male subjects. One subject was withdrawn because of a mild adverse event (increased hepatic enzyme levels) that resolved without intervention. Repeated administration of esaxerenone increased midazolam AUClast, AUCinf, and Cmax by about 1.2-fold (1.201, 1.201, and 1.224, respectively) compared with administration of midazolam alone. However, repeated administration of esaxerenone did not affect the elimination half-life of midazolam (2.86 versus 2.63 h with and without esaxerenone). There were no safety concerns associated with concomitant administration of esaxerenone and midazolam.ConclusionsEsaxerenone 5 mg/day had no clinically significant effect on midazolam pharmacokinetics and was not associated with any safety issues. Esaxerenone can be concomitantly administered with drugs of CYP3A substrates without dose adjustments.Clinical trial registrationJapiCTI-152832.

Dosing Recommendations for Vancomycin in Children and Adolescents with Varying Levels of Obesity and Renal Dysfunction: a Population Pharmacokinetic Study in 1892 Children Aged 1\u201318 Years

Vancomycin is an effective but potentially nephrotoxic antibiotic commonly used for severe infections. Dosing guidelines for vancomycin in obese children and adolescents with or without renal impairment are currently lacking. This study describes the pharmacokinetics of vancomycin in a large pediatric cohort with varying degrees of obesity and renal function to design practical dosing guidelines for this population. A multi-center retrospective population pharmacokinetic study was conducted using data from patients aged 1−18 years who received >1 dose of vancomycin and had ≥1 vancomycin concentration measured between January 2006 and December 2012. Besides pharmacokinetic data, age, gender, body weight, creatinine clearance (CLcr, bedside Schwartz equation), ward, race, and neutropenic status were collected. Population pharmacokinetic analysis and simulations were performed using NONMEM7.4. A total of 1892 patients (5524 samples) were included, with total body weight (TBW) ranging 6−188 kg (1344 normal weight, 247 overweight, and 301 obese patients) and CLcr down to 8.6 mL/min/1.73 m2. The two-compartment model, with clearance (CL) significantly increasing with TBW and CLcr, central and peripheral volume of distribution and inter-compartmental clearance increasing with TBW, performed well for all age, weight, and renal function ranges. A dosing guideline is proposed that integrates body weight and CLcr resulting in effective and safe exposures across all ages, body weight, and renal functions in the pediatric population. We have characterized the full pharmacokinetic profile of vancomycin in obese children and adolescents aged 1−18 years and propose a practical dosing guideline that integrates both body weight and renal function.

Development of a population pharmacokinetic model and Bayesian estimators for isoniazid in Tunisian tuberculosis patients.

This study aimed to develop a population pharmacokinetic model using fullpharmacokinetic (PK) profiles of isoniazid (INH) taking into account demographic and genetic covariates and to develop Bayesian estimators for predicting INH area under the curve (AUC) in Tunisian tuberculosis patients. The INH concentrations in the building data set were fitted using a one- to three-compartment model. The impact of the different covariates was assessed on the PK parameters of the best model. The best limited sampling strategy (LSS) for estimating the INH AUC was selected by comparing the predicted values to an independent data set. INH PK was best described using a three-compartment model with lag-time absorption. The different studied covariates did not have any impact on the PK parameters of the building model. The Bayesian estimation using one-point concentrations gave the lowest values of prediction errors for the C3 LSS model. This model could be sufficient in routine activity for INH monitoring in this population.

Limited Sampling Strategy for Determination of Ibrutinib Plasma Exposure: Joint Analyses with Metabolite Data.

Therapeutic drug monitoring of ibrutinib is based on the area under the curve of concentration vs. time (AUCIBRU) instead of trough concentration (Cmin,ss) because of a limited accumulation in plasma. Our objective was to identify a limited sampling strategy (LSS) to estimate AUCIBRU associated with Bayesian estimation. The actual AUCIBRU of 85 patients was determined by the Bayesian analysis of the full pharmacokinetic profile of ibrutinib concentrations (pre-dose T0 and 0.5, 1, 2, 4 and 6 h post-dose) and experimental AUCIBRU were derived considering combinations of one to four sampling times. The T0–1–2–4 design was the most accurate LSS (root-mean-square error RMSE = 11.0%), and three-point strategies removing the 1 h or 2 h points (RMSE = 22.7% and 14.5%, respectively) also showed good accuracy. The correlation between the actual AUCIBRU and Cmin,ss was poor (r2 = 0.25). The joint analysis of dihydrodiol-ibrutinib metabolite concentrations did not improve the predictive performance of AUCIBRU. These results were confirmed in a prospective validation cohort (n = 27 patients). At least three samples, within the pre-dose and 4 h post-dose period, are necessary to estimate ibrutinib exposure accurately.

Pharmacokinetic/pharmacodynamic analysis of romidepsin used as an HIV latency reversing agent.

To develop a population pharmacokinetic model for romidepsin given as an HIV latency reversing agent (LRA) and to explore the relationship between romidepsin exposure and its in vivo effects on viral gene expression and antiviral immunity. A population pharmacokinetic analysis was performed in 15 HIV-1-infected patients who received three weekly infusions of romidepsin (5 mg/m2) within the BCN02 clinical trial. A full pharmacokinetic profile was obtained for each participant at the first dose, and additional samples thereafter. A population pharmacokinetic model was developed. Bayesian estimates of the individual pharmacokinetic parameters of romidepsin were used to simulate individual time-concentration curves on each occasion. The relationship between romidepsin AUC0-∞ and its in vivo effects was assessed. Romidepsin pharmacokinetics were best described by a three-compartment model with linear kinetics. Body weight influenced romidepsin disposition. A significant relationship was observed between romidepsin AUC0-∞ and increases in expression of exhaustion markers by CD4+ and CD8+ T cells and apoptosis markers in CD4+, but not with histone acetylation levels or HIV-1 cell-associated RNA in CD4+ T cells. For each increase of 100 ng·h/mL in romidepsin AUC0-∞, CD4+ counts decreased by a mean (95% CI) of 74 (42-94) cells/mm3 after dosing. A population model describing the pharmacokinetics of romidepsin as an HIV LRA was developed. Higher exposure to romidepsin resulted in higher expression of apoptosis markers and declines in CD4+ count but did not increase viral reactivation levels. These observations have important implications for the optimization of effective kick-and-kill strategies for an HIV-1 cure.

Real‐time pharmacokinetic and pharmacodynamic measurements of drugs within the brains of freely behaving rats.

The drug cocaine evokes complex neurochemical responses that mediate their influence of neural circuits underlying behavioral control, such as the dopamine pathways that we now know drive reward anticipation and locomotor behavior. In contrast, the anesthetic drug procaine functions as both a local anesthetic in the periphery, and a general anesthetic when it reaches the brain, affecting breathing, heart rate, and locomotion. However, the time resolution with which existing methods can measure these drugs is orders of magnitude poorer than the resolution with which physiological responses to these drugs occur. In response to this problem, our group has recently developed a new technology, electrochemical aptamer‐based sensors (E‐AB sensors), which are the size of a human hair and can detect physiologically relevant concentrations of specific drugs in‐situ, in awake, freely behaving animals. Here, we tested this new technology on rats that have been administered either cocaine or procaine intravenously and measured the concentrations of these drugs within the lateral ventricle concurrent with monitoring locomotor activity. We successfully measured the concentration of cocaine and procaine every 10 s for 2 hours and generated a full pharmacokinetic and pharmacodynamic profile for these drugs within the lateral ventricle. As cocaine concentrations increased (from 0 to 5 μM), they directly corresponded with increased locomotor activity and stereotypy, whereas increased levels of procaine in the lateral ventricle coincided with decreased heart rate, oxygen saturation (SPO2), and locomotion. In conclusion, we have developed a novel, potentially revolutionary, technology that can measure the pharmacokinetics and pharmacodynamics of psychoactive drugs within the brains of awake, freely behaving animals.Support or Funding InformationFunding was provided by the National Institutes of Health R01EB022015 and the W.M. Keck foundation.

1550. PK-PD Relationship and PK Driver of Efficacy of the Novel Antibacterial Lysin Exebacase (CF-301) in Pre-Clinical Models

BackgroundExebacase (CF-301) is a novel lysin with rapid bacteriolytic and anti-biofilm activity against S. aureus, pronounced synergy with antibiotics and low propensity for resistance. Exebacase has undergone Phase 1–2 trials. This work was to develop pharmacokinetic (PK) model in animal and determine the relationship between exebacase exposure and efficacy in animals.MethodsPK data in 592 animals (4 species) included in population PK model. A range of linear and nonlinear mammillary models with allometric scaling fitted to the PK data using NONMEM and the most parsimonious model was selected by improvement in objective function value (P < 0.01). To evaluate efficacy, 349 animals with 177 mice (neutropenic thigh infection) and 172 rabbits (aortic valve infective endocarditis were treated with exebacase in addition to suboptimal doses of daptomycin (DAP). Full PK profiles were simulated for individual animals. Fifty-nine dosing regimens of exebacase in mice (0–90 mg/kg) and 18 regimens in rabbits (0–1.4 mg/kg) with q24h, q12h and q8h frequencies. Relationship between AUC/MIC, Cmax/MIC, T> MIC, and log-CFU was examined using a range of functions by comparing residual standard error (RSE).Results3-compartment model with allometric scaling best described the PK data and was validated by bootstrap and Goodness of Fit. Maximum drop in log10CFU/g in target tissues was at AUC/MIC< 0.2 for exebacase when added to DAP that was associated with CF reduction of -5 logs in rabbits (Figure (a)) with similar magnitudes in cardiac vegetations, kidney and spleen, and -4 logs in mice (Figure (b)). Treatment with DAP alone had log10CFU reduction of -1 in mice; and -2 in rabbits. AUC/MIC was an appropriate predictor of CFU reductions.ConclusionPK model adequately described the data for 4 animal species. Exebacase addition to DAP has a synergistic effect on efficacy measured by CFU reductions in target tissues in the animal models. Results support previously presented determinations of AUC/MIC as predictor of efficacy. Maximum reductions in CFU in rabbits and mice were observed at AUC/MIC ratios <0.2. These results further indicate that rabbit is the most appropriate efficacy model with MICs and antibacterial activity reflective of previously reported observations in human serum. Disclosures All authors: No reported disclosures.

Abstract 3511: Exploration of pre-clinical relationships between pharmacokinetics, pharmacodynamics and tumor volume for the novel DNA-PK inhibitor AZD7648

Abstract AZD7648 is a potent and highly selective inhibitor of DNA-dependent protein kinase (DNA-PK) that has been nominated for clinical development. DNA-PK is a nuclear serine/threonine protein kinase complex involved in DNA damage repair, and a key component of the non-homologous end joining repair mechanism of double strand breaks (DSBs). This work aimed to explore the relationships between pharmacokinetics (PK), pharmacodynamics (PD) and xenograft tumor volume from pre-clinical studies, in order to define PD requirements for pre-clinical efficacy, and to estimate a target clinical dose for AZD7648 in combination with DSB-inducing agents such as olaparib or pegylated liposomal doxorubicin (PLD). A population-based modelling approach was used to explore the PK of AZD7648 in mice. The PK model was developed using data from full PK profiles (multiple longitudinal samples per mouse), and validated against terminal sample PK data. The potential influences of strain-dependence, time non-linearity, and interaction with olaparib on the pharmacokinetics of AZD7648 were investigated. Direct and indirect inhibition PD models were fitted to the responses of biomarkers describing target engagement (pDNA-PK) or proximal downstream effects (pRPA32 (S4/8) and γH2AX). A compartmental model accurately described AZD7648 PK in mice, with rapid absorption, dose-proportional PK across the range of doses tested, time-independent parameters and no effect of olaparib co-dosing on AZD7648 PK. The PD of proximal target engagement biomarkers were best described with an Imax model with very rapid turnover (&amp;lt;10 minutes), which showed there was negligible delay (due to tumor distribution or pharmacology) and effectively a direct relationship between systemic PK and xenograft biomarker inhibition. Across a number of FaDu ATM KO and BT474c xenograft tumor studies, the duration of cover over IC90 correlated with efficacy in combination with olaparib or PLD, demonstrating the importance of inhibiting DNA-PK for an extended duration in each dosing period. This result was applied to define a target level and duration of PD inhibition, and, when combined with predicted human PK behaviour, a target clinical dose for AZD7648 in combination with DSB-inducing agents to inform the clinical investigation of AZD7648. Citation Format: Michael Davies, Joost de Jongh, Emma Dean, Jacquelline H. Fok, Frederick W. Goldberg, Neil James, Ankur Karmokar, Antonio Ramos-Montoya, Anna Staniszewska, Andy Sykes, Tamara van Steeg, Elaine Cadogan. Exploration of pre-clinical relationships between pharmacokinetics, pharmacodynamics and tumor volume for the novel DNA-PK inhibitor AZD7648 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3511.

Tobramycin Clearance Is Best Described by Renal Function Estimates in Obese and Non-obese Individuals: Results of a Prospective Rich Sampling Pharmacokinetic Study

PurposeTobramycin is an aminoglycoside antibiotic of which the 24 h exposure correlates with efficacy. Recently, we found that clearance of the aminoglycoside gentamicin correlates with total body weight (TBW). In this study, we investigate the full pharmacokinetic profile of tobramycin in obese and non-obese individuals with normal renal function.MethodsMorbidly obese individuals (n = 20) undergoing bariatric surgery and non-obese healthy volunteers (n = 8), with TBW ranging 57–194 kg, received an IV dose of tobramycin with plasma concentrations measured over 24 h (n = 10 per individual). Statistical analysis, modelling and simulations were performed using NONMEM.ResultsIn a two-compartment model, TBW was the best predictor for central volume of distribution (p < 0.001). For clearance, MDRD (de-indexed for body surface area) was identified as best covariate (p < 0.001), and was superior over TBW ((p < 0.05). Other renal function estimates (24 h urine GFR and de-indexed CKD-EPI) led to similar results as MDRD (all p < 0.001)).ConclusionsIn obese and non-obese individuals with normal renal function, renal function estimates such as MDRD were identified as best predictors for tobramycin clearance, which may imply that other processes are involved in clearance of tobramycin versus gentamicin. To ensure similar exposure across body weights, we propose a MDRD-based dosing nomogram for obese patients.

Pharmacokinetics of dolutegravir 100 mg once daily with rifampicin

Tuberculosis (TB) causes 25% of all deaths among individuals infected with human immunodeficiency virus (HIV). Rifampicin (RIF) is a potent inducer of drug metabolizing enzymes and drug transporters, and co-administration with dolutegravir (DTG) reduces DTG exposure; this can be overcome by doubling the DTG dose to 50 mg twice daily. This study investigated the effect of RIF on DTG exposure when dosed at 100 mg once daily, which could provide an easier option than 50 mg twice daily. An open label, pharmacokinetic (PK) study was undertaken. Healthy HIV-negative subjects received DTG 50 mg for 7 days (PK1), DTG 100 mg for 7 days (PK2), RIF for 14 days, DTG 50 mg + RIF for 7 days (PK3) and DTG 100 mg + RIF for 7 days (PK4). Steady-state full DTG PK profiles were evaluated. DTG geometric mean ratios (GMRs) of PK3/PK1 of maximum concentration (Cmax), area under curve (AUC24h) and 24-h post-dose concentration (C24h) were 0.65 [90% confidence interval (CI) 0.55-0.75], 0.44 (90% CI 0.37-0.52) and 0.15 (0.13-90% CI 0.17), respectively. GMRs of PK4/PK1 Cmax, AUC24h and C24h were 1.09 (90% CI 0.97-1.21), 0.74 (90% CI 0.64-0.86) and 0.24 (90% CI 0.20-0.28), respectively. Median C24h of DTG 50 mg + RIF and DTG 100 mg + RIF were 251 (range 129-706) ng/mL and 140 (range 73-426) ng/mL, respectively. Although there were substantial reductions in DTG C24h when co-administered with RIF, concentrations of both DTG 50 mg and 100 mg once daily with RIF were still above the protein-binding-adjusted IC90 (drug concentration required to inhibit 90% of in-vitro viral replication) of 64 ng/mL. Further studies in HIV-TB co-infected individuals are warranted to confirm these results.

Synthetic Cannabinoid Hydroxypentyl Metabolites Retain Efficacy at Human Cannabinoid Receptors.

Synthetic cannabinoids (SCs) are novel psychoactive substances that are easily acquired, widely abused as a substitute for cannabis, and associated with cardiotoxicity and seizures. Although the structural bases of these compounds are scaffolds with known affinity and efficacy at the human cannabinoid type-1 receptor (hCB1), upon ingestion or inhalation they can be metabolized to multiple chemical entities of unknown pharmacological activity. A large proportion of these metabolites are hydroxylated on the pentyl chain, a key substituent that determines receptor affinity and selectivity. Thus, the pharmacology of SC metabolites may be an important component in understanding the in vivo effects of SCs. We examined nine SCs (AB-PINACA, 5F-AB-PINACA, ADB/MDMB-PINACA, 5F-ADB, 5F-CUMYL-PINACA, AMB-PINACA, 5F-AMB, APINACA, and 5F-APINACA) and their hydroxypentyl (either 4-OH or 5-OH) metabolites in [3H]CP55,940 receptor binding and the [35S]GTPγS functional assay to determine the extent to which these metabolites retain activity at cannabinoid receptors. All of the SCs tested exhibited high affinity (<10 nM) and efficacy for hCB1 and hCB2 The majority of the hydroxypentyl metabolites retained full efficacy at hCB1 and hCB2, albeit with reduced affinity and potency, and exhibited greater binding selectivity for hCB2 These data suggest that phase I metabolites may be contributing to the in vivo pharmacology and toxicology of abused SCs. Considering this and previous reports demonstrating that metabolites retain efficacy at the hCB1 receptor, the full pharmacokinetic profiles of the parent compounds and their metabolites need to be considered in terms of the pharmacological effects and time course associated with these drugs.

Population Pharmacokinetics and Bayesian Estimation of Mycophenolic Acid Exposure in Chinese Renal Allograft Recipients After Administration of EC‐MPS

The aim of the present study is to establish a population pharmacokinetic (PPK) model of mycophenolic acid (MPA) and limited sampling strategy models for the estimation of MPA exposure in Chinese adult renal allograft recipients following oral administration of enteric coated mycophenolate sodium (EC-MPS). A total of 74 sets of full pharmacokinetic profiles and 47 sets of MPA-sparing samples were collected from 102 renal transplant recipients who received oral EC-MPS. The MPA concentration was determined by an enzyme-multiplied immunoassay technique, and the pathophysiologic data were recorded. The PPK model was constructed using nonlinear mixed-effects modeling, and the limited sampling strategy models for MPA were established by using multiple regression analysis and the maximum a posteriori Bayesian assay based on 2 to 4 sampling time points following EC-MPS administration. The pharmacokinetics of MPA were best described by a 2-compartment model with a first-order absorption process and a lag time of absorption. The clearance of MPA was 12.3 ± 1.14 L/h. Comedicating with cyclosporine A was found to have a significant impact on the clearance/bioavailability of MPA (P < .01). Sampling strategies consisted of plasma concentration at 1.5, 2, 4 (C1.5-C2-C4) hours and 1.5, 2, 4, 6 (C1.5-C2-C4-C6) hours after EC-MPS administration were shown to be suitable for the estimation of the MPA area under the concentration-time curve in these patients. The PPK model was acceptable and can describe the pharmacokinetics of MPA in Chinese renal transplant recipients administered EC-MPS. The area under the concentration-time curve of MPA in Chinese renal transplant recipients could be estimated through a limited sampling strategy method, based on which individualized immunosuppressive regimens could be designed.