Published Pharmacokinetic Research Articles

Getting the dose right using physiologically-based pharmacokinetic modeling: dexamethasone to prevent post-extubation stridor in children as proof of concept.

Critically ill patients show large variability in drug disposition due to e.g., age, size, disease and treatment modalities. Physiologically-based pharmacokinetic (PBPK) models can be used to design individualized dosing regimens taking this into account. Dexamethasone, prescribed for the prevention post-extubation stridor (PES), is metabolized by the drug metabolizing enzyme CYP3A. As CYP3A4 undergoes major changes during childhood, we aimed to develop age-appropriate dosing recommendations for children of dexamethasone for PES, as proof of concept for PBPK modeling to individualize dosing for critically ill patients. All simulations were conducted in Simcyp™ v21 (a population-based PBPK modeling platform), using an available dexamethasone compound model and pediatric population model in which CYP3A4 ontogeny is incorporated. Published pharmacokinetic (PK) data was used for model verification. Evidence for the dose to prevent post-extubation stridor was strongest for 2-6 year old children, hence simulated drug concentrations resulting from this dose from this age group were targeted when simulating age-appropriate doses for the whole pediatric age range. Dexamethasone plasma concentrations upon single and multiple intravenous administration were predicted adequately across the pediatric age range. Exposure-matched predictions of dexamethasone PK indicated that doses (in mg/kg) for the 2-6 years olds can be applied in 3 month-2 year old children, whereas lower doses are needed in children of other age groups (60% lower for 0-2 weeks, 40% lower for 2-4 weeks, 20% lower for 1-3 months, 20% lower for 6-12 year olds, 40% lower for 12-18 years olds). We show that PBPK modeling is a valuable tool that can be used to develop model-informed recommendations using dexamethasone to prevent PES in children. Based on exposure matching, the dose of dexamethasone should be reduced compared to commonly used doses, in infants <3 months and children ≥6 years, reflecting age-related variation in drug disposition. PBPK modeling is an promising tool to optimize dosing of critically ill patients.

Pharmacokinetics and dialytic clearance of baricitinib during in vivo continuous venovenous haemodialysis in a patient with COVID-19

ObjectivesTo date, there are no published pharmacokinetic (PK) data for baricitinib in critically ill patients requiring continuous renal replacement therapy. This paper describes in detail the plasma PK and dialytic clearance of baricitinib in a patient infected with coronavirus disease 2019 (COVID-19) requiring continuous renal replacement therapy in order to suggest dosing strategies in this population. MethodsBaricitinib 2 mg daily was used for the treatment of COVID-19 in a critically ill patient on continuous venovenous haemodialysis (CVVHD). Prefiltration plasma drug concentrations of baricitinib were measured at hours 1, 2, 12, and 24 after drug administration. Postfiltration and ultrafiltrate concentrations were collected at hour 24. ResultsPlasma PK parameters of baricitinib in this patient were as follows: maximum plasma concentration (Cmax), 20.98 ng/mL; minimum plasma concentration (Cmin), 9.84 ng/mL; half-life (t1/2), 23.85 h; apparent volume of distribution at the steady state (Vss), 99.42 L; total clearance at the steady state (CLss), 2.89 L/h; and area under the concentration-time curve (AUC0–∞), 692.14 ng · h/mL. The saturation coefficient for baricitinib at 24 h after administration was 0.607. The transmembrane clearance of baricitinib by CVVHD running at a flow rate of 2 L/h was 1.21 L/h, representing 41.9% of the total clearance of baricitinib. ConclusionsIn a critically ill COVID-19 patient on CVVHD, a 2-mg dose of baricitinib achieves a Cmax comparable with healthy subjects, but total clearance was reduced to about 20%. Larger studies exploring multiple patients and dialysis modes are needed to determine the optimal dosing strategy for baricitinib in this patient population.

Optimal dosing of enoxaparin in overweight and obese children.

Current enoxaparin dosing guidelines in children are based on total body weight. This is potentially inappropriate in obese children as it may overestimate the drug clearance. Current evidence suggests that obese children may require lower initial doses of enoxaparin, therefore the aim of this work was to characterise the pharmacokinetics of enoxaparin in obese children and to propose a more appropriate dosing regimen. Data from 196 unique encounters of 160 children who received enoxaparin treatment doses were analysed. Enoxaparin concentration was quantified using the chromogenic anti factor Xa (anti-Xa) assay. Patients provided a total of 552 anti-Xa samples. Existing published pharmacokinetic (PK) models were fitted and evaluated against our dataset using prediction-corrected visual predictive check plots (pcVPCs). A PK model was fitted using a nonlinear mixed-effects modelling approach. The fitted model was used to evaluate the current standard dosing and identify an optimal dosing regimen for obese children. Published models of enoxaparin pharmacokinetics in children did not capture the pharmacokinetics of enoxaparin in obese children as shown by pcVPCs. A one-compartment model with linear elimination best described the pharmacokinetics of enoxaparin. Allometrically scaled fat-free mass with an estimated exponent of 0.712 (CI 0.66-0.76) was the most influential covariate on clearance while linear fat-free mass was selected as the covariate on volume. Simulations from the model showed that fat-free mass-based dosing could achieve the target anti-Xa activity at steady state in 77.5% and 78.2% of obese and normal-weight children, respectively, compared to 65.2% and 75.5% for standard total body weight-based dosing. A population PK model that describes the time course of anti-Xa activity of enoxaparin was developed in a paediatric population. Based on this model, a unified dosing regimen was proposed that will potentially improve the success rate of target attainment in overweight/obese patients without the need for patient body size categorisation. Therefore, prospective validation of the proposed approach is warranted.

Pharmacokinetic Studies in Elasmobranchs: Meloxicam Administered at 0.5 mg/kg Using Intravenous, Intramuscular, and Oral Routes to Nusehound Sharks (Scyliorhinus stellaris).

Infectious and inflammatory diseases are the most frequently diagnosed pathologies in elasmobranchs maintained under human care. Non-steroidal anti-inflammatory drugs (NSAIDs) are frequently used in veterinary medicine for their anti-inflammatory, analgesic, and antipyretic properties. Meloxicam is a commonly prescribed NSAID in elasmobranchs, but there are still no published pharmacokinetic (PK) studies supporting its use in this group of animals. In this study, meloxicam was administered at a single dose of 0.5 mg/kg to eight healthy adult nursehound sharks (Scyliorhinus stellaris) intravenously (IV), intramuscularly (IM), and orally (PO), with a minimum 4-week washout period between administrations. Blood samples were obtained both beforehand and at predetermined times after each administration. Plasma concentrations were measured using a validated high performance liquid chromatography method, and PK data was obtained using a non-compartmental analysis. Meloxicam administered orally did not produce detectable concentrations in blood plasma, while mean peak plasma concentration was 0.38 ± 0.08 μg/ml after IM administration. The mean terminal half-life was 10.71 ± 2.77 h and 11.27 ± 3.96 h for IV and IM injections, respectively. The area under the curve extrapolated to infinity was 11.37 ± 2.29 h·μg/ml after IV injections and 5.98 ± 0.90 h·μg/ml after IM injections. Meloxicam administered IM had a mean absolute bioavailability of 56.22 ± 13.29%. These numbers support meloxicam as a promising drug to be used IM in nursehounds, questions the efficacy of its single PO use in elasmobranchs, elucidate the need for higher dosage regimes, and evidence the need for further PK studies in sharks and rays.

Elevated acute phase proteins affect pharmacokinetics in COVID-19 trials: Lessons from the CounterCOVID - imatinib study.

This study aimed to determine whether published pharmacokinetic (PK) models can adequately predict the PK profile of imatinib in a new indication, such as coronavirus disease 2019 (COVID‐19). Total (bound + unbound) and unbound imatinib plasma concentrations obtained from 134 patients with COVID‐19 participating in the CounterCovid study and from an historical dataset of 20 patients with gastrointestinal stromal tumor (GIST) and 85 patients with chronic myeloid leukemia (CML) were compared. Total imatinib area under the concentration time curve (AUC), maximum concentration (Cmax) and trough concentration (Ctrough) were 2.32‐fold (95% confidence interval [CI] 1.34–3.29), 2.31‐fold (95% CI 1.33–3.29), and 2.32‐fold (95% CI 1.11–3.53) lower, respectively, for patients with CML/GIST compared with patients with COVID‐19, whereas unbound concentrations were comparable among groups. Inclusion of alpha1‐acid glycoprotein (AAG) concentrations measured in patients with COVID‐19 into a previously published model developed to predict free imatinib concentrations in patients with GIST using total imatinib and plasma AAG concentration measurements (AAG‐PK‐Model) gave an estimated mean (SD) prediction error (PE) of −20% (31%) for total and −7.0% (56%) for unbound concentrations. Further covariate modeling with this combined dataset showed that in addition to AAG; age, bodyweight, albumin, CRP, and intensive care unit admission were predictive of total imatinib oral clearance. In conclusion, high total and unaltered unbound concentrations of imatinib in COVID‐19 compared to CML/GIST were a result of variability in acute phase proteins. This is a textbook example of how failure to take into account differences in plasma protein binding and the unbound fraction when interpreting PK of highly protein bound drugs, such as imatinib, could lead to selection of a dose with suboptimal efficacy in patients with COVID‐19.

Safety, Pharmacokinetics and Pharmacodynamics of Spectrum Red Softgels in Healthy Participants.

Due to a lack of published pharmacokinetic (PK) and/or pharmacodynamic (PD) data, informed physician and patient decision-making surrounding appropriate dosing of cannabis for medical purposes is limited. This Phase 1, multiple-dose study evaluated the safety, tolerability, PK and PD of Spectrum Red softgels (2.5 mg Δ9-tetrahydrocannabinol (THC) and <0.25 mg cannabidiol (CBD)). Participants (n = 41) were randomized to one of five groups: 5 mg THC and 0.06 mg CBD daily (Treatment A), 10 mg THC and 0.12 mg CBD daily (Treatment B), 15 mg THC and 0.18 mg CBD daily (Treatment C), 20 mg THC and 0.24 mg CBD daily (Treatment D) or placebo. Study medication was administered in divided doses, every 12 h, ∼60 min after a standardized meal, for 7 consecutive days. All treatment-emergent adverse events (TEAEs) (65/65) were of mild-to-moderate severity; none was serious. The highest number of TEAEs (30/65) occurred on the first day of treatment. The most common TEAEs included somnolence, lethargy and headache (reported by eight, seven and five participants, respectively). On Day 7, maximum observed plasma concentration of 11-carboxy-THC increased by 2.0- and 2.5-fold as the dose doubled between Treatments A and B and between Treatments B and D, respectively. Mean peak post-treatment ratings of self-reported subjective effects of ‘feel any effect’ and ‘dazed’ differed between Treatment D and placebo on Days 1, 3 and 7. Over a week of twice-daily dosing of Spectrum Red softgels, daily doses of THC up to 20 mg and of CBD up to 0.24 mg were generally safe and became better tolerated after the first day of treatment. A prudent approach to improve tolerability with Spectrum Red softgels might involve initial daily doses no higher than 10 mg THC and 0.12 mg CBD in divided doses, with titration upward over time as needed based on tolerability.

Safety, Pharmacokinetics and Pharmacodynamics of Spectrum Yellow Oil in Healthy Participants.

Due to a lack of published pharmacokinetic (PK) and/or pharmacodynamic (PD) data, decision-making surrounding appropriate dosing of cannabis used for medical purposes is limited. This multiple-dose study evaluated the safety, tolerability, PK and PD of Spectrum Yellow oil [20 mg/mL cannabidiol (CBD)/<1 mg/mL ∆9-tetrahydrocannabinol (THC)]. Participants (n = 43) were randomized to one of five groups: 120 mg CBD and 5.4 mg THC daily, 240 mg CBD and 10.8 mg THC daily, 360 mg CBD and 16.2 mg THC daily, 480 mg CBD and 21.6 mg THC daily or placebo. Study medication was administered every 12 h for 7 consecutive days. Treatment-emergent adverse events (TEAEs); plasma and urine concentrations of THC, CBD and metabolites; and self-reported subjective effects were collected. Nearly all TEAEs (44/45) were of mild or moderate severity; none was serious. The highest incidence of TEAEs (67%) was in the two higher-dose treatment groups. The highest number of TEAEs (17/45) occurred on the first treatment day. Steady-state plasma CBD concentrations were reached by Day 7. On Day 7, CBD exposure showed dose proportionality (AUC0–t slope = 1.03 [0.70, 1.36], Cmax slope = 0.92 [0.53, 1.31]). Most plasma THC concentrations were below the limit of quantification. Across Days 1 and 7, there were no consistent differences in subjective effects between placebo and active study medication. A prudent approach to improve tolerability with Spectrum Yellow oil might involve initial doses no higher than 240 mg total CBD and 10.8 mg total THC daily in divided doses, with titration upward over time as needed based on tolerability.

Tentative clinical breakpoints and epidemiological cut-off values of nemonoxacin for Streptococcus pneumoniae and Staphylococcus aureus isolates associated with community-acquired pneumonia

ObjectivesTo determine the minimum inhibitory concentration (MIC) distribution, epidemiological cut-off (ECOFF) values and clinical breakpoints (CBPs) of nemonoxacin, a non-fluorinated quinolone, for community-acquired pneumonia (CAP)-related Streptococcus pneumoniae and Staphylococcus aureus. MethodsWe pooled the susceptibility and clinical data of CAP patients enrolled in five clinical trials conducted in three countries from 2006 to 2017. Published pharmacokinetic (PK) profiles of oral (500 mg) and intravenous (IV) (500, 650 and 750 mg) nemonoxacin formulations and pharmacodynamic (PD) parameters of the two aforementioned CAP-related Gram-positive cocci (GPC) were used to determine plausible CBPs. Moreover, nemonoxacin MIC distributions of CAP-relatedS. pneumoniae (n = 1800) and S. aureus (n = 2000) isolates were obtained to evaluate ECOFF values using a visual estimation approach and ECOFFinder. ResultsMore than 92% of patients with CAP caused byS. pneumoniae or S. aureus with nemonoxacin MICs ≤ 0.25 mg/L presented positive clinical and microbiological outcomes. The ECOFF, MIC90 and MIC99 values of nemonoxacin were, respectively, 0.06, 0.125 and 1 mg/L for S. pneumoniae and 0.125, 1 and 8 mg/L for S. aureus. Based on differences in the PK profiles of oral and IV formulations, PD parameters of nemonoxacin for these CAP-GPC and clinical in vivo efficacy data, tentative CBPs of 0.5, 0.5 and 1 mg/L, respectively, were established for the 500 mg oral and 500 mg and 750 mg IV nemonoxacin formulations for S. pneumoniae, and 0.25, 0.5 and 1 mg/L for S. aureus. ConclusionThis study provides plausible nemonoxacin CBPs for two important CAP-GPC.

In vitro Metabolism studies of Catechol‐Containing Natural Products and Analogues

Many biologically active natural products contain phenol groups that are prone to rapid phase‐II metabolism. In order to better understand the structural basis for these metabolic transformations, we have investigated the in vitro metabolism of rooperol, a bis‐catechol with anti‐cancer activity, and caffeic acid phenethyl amide (CAPA), a synthetic analog of a natural product with antioxidant and cytoprotective activities. In the presence of pig liver microsomes supplemented with UDP‐glucuronic acid, both of these catechols undergo rapid phase‐II metabolism to form mono‐ (CAPA and rooperol) and bis‐ (rooperol) glucuronide metabolites. The identity of these metabolites was determined by HPLC‐MS. We followed the kinetics of these in vitro metabolism reactions using HPLC. In both cases, the disappearance of the compound over time corresponded to a first‐order process with half‐life of 4.0 ± 0.5 min for rooperol and 5.1 ± 0.8 min for CAPA. In the case of rooperol, this data is in agreement with previously published pharmacokinetic (PK) studies in humans, in which only phase‐II metabolites were detected after oral administration, as well as PK studies in baboons which also report rapid phase‐II metabolism following IV administration. While human or non‐human primate PK data for CAPA have not been reported, our data suggest that this compound will also suffer from rapid phase‐II metabolism, and thus more metabolically stable analogs of both rooperol and CAPA are required.Support or Funding InformationThis research was supported by the U.S. Department of Education HSI STEM program (841.031c), Award #P021C160036The Robert and Ella Owens Medical Research Foundation

Dosing of Antimicrobials in the Neonatal Intensive Care Unit: Does Clinical Practice Reflect Pharmacokinetics-based Recommendations?

We sought to compare meropenem and fluconazole dosing in the neonatal intensive care unit with recommendations based on published pharmacokinetic (PK) studies in infants. We performed an observational cohort study of infants <90 days postnatal age who received a course of meropenem or fluconazole who were treated in neonatal intensive care units managed by the Pediatrix Medical Group (1997-2016). We defined any dose amount from 80% to 120% of the published recommendation to constitute an appropriate dose of either antimicrobial. We calculated the percentage of appropriately dosed courses overall and by discharge year. We then evaluated the change in appropriate dosing over time using a nonparametric test of trend to evaluate the proportion of appropriately dosed courses of each antimicrobial by discharge year. A total of 3608 infants were administered 2025 courses of meropenem and 1201 courses of fluconazole. Of all meropenem courses, 32% were dosed appropriately (increased significantly over time; P = 0.01), while 17% of fluconazole courses were dosed appropriately (increased significantly over time; P = 0.01). Median dosing for both meropenem and fluconazole was at or below recommendations; therefore, under-dosing was more common. There was marked discordance between actual fluconazole and meropenem dosing and dosing recommendation in PK publications, yet adherence to PK-based doses showed improvement over time.

Impact of Target Cell Number on Target Cell and Tissue Dose for Antibody-Mediated Delivery of Alpha-Emitters

225Ac-Lintuzumab- is an alpha-particle emitter labeled anti-CD33 antibody that is in clinical trial evaluation for the treatment of patients with leukemia and myelodysplastic syndrome (MDS). It is also being developed as a targeted conditioning regimen to irradiate and ablate the bone marrow as part of a marrow transplant treatment regimen. We examine the influence of target cell number on the absorbed dose to organs considered critical from the perspective of acute toxicity or late stage or stochastic effects A previously published pharmacokinetic (PK) model [1] is used to obtain the distribution of 225Ac -labeled antibody for 109 up to 1012 antigen-positive cells corresponding approximately to a range of 1 to 1000 g cells. The PK output was integrated to provide time integrated activity (TIA) input for dosimetry. Absorbed dose calculations were performed using the MIRD Committee S-value based method as described in pamphlet 21 [2]. The International Commission on Radiological Protection (ICRP) recently released absorbed fractions for a new series of phantoms that include far more tissues than were previously available [3]. These were used to perform the dosimetry calculations provided in this report. Decay schemes and half-lives for 225Ac were obtained from ICRP publication 107 [4]. A detailed comparison of the results obtained using OLINDA and the new set of ICRP data has been published [5]. The results for different numbers of antigen positive cells are shown below. Absorbed dose (mGy/MBq) Ag+ cells marrow kidneys liver lungs 109 402 2939 468 416 1010 1150 2385 431 337 1011 2444 869 333 123 1012 2708 157 289 22 The results obtained are derived from model-based simulations of anti-CD33 antibody pharmacokinetics in patients with leukemia. The model makes it possible to project the impact of different antigen-positive numbers of cells (e.g., tumor burdens) on pharmacokinetics and dosimetry. The low red marrow and high kidney dose under the condition of 109 antigen-positive cells reflects the low retention of 225Ac-Ab in the marrow when there are very few targets in the marrow. The high kidney dose occurs because low target cell number reduces the capture of free 213Bi by internalization. The model assumes that 50% of free 213Bi in circulation will decay in the kidneys. The model suggests that organ absorbed doses will vary based on the number of antigen positive cells.

A Retrospective Analysis of Probability of Target Attainment in Community-Acquired Pneumonia: Ceftaroline Fosamil Versus Comparators

IntroductionThis retrospective analysis compares the probability of target attainment (PTA) for ceftriaxone, levofloxacin and ceftaroline fosamil against Staphylococcus aureus, Streptococcus pneumoniae and Haemophilus influenzae in a representative patient population with moderate-to-severe community-acquired pneumonia (CAP).MethodsPublished pharmacokinetic (PK) models for levofloxacin and ceftriaxone, and an existing model for ceftaroline, were used with standard dosage regimens for simulating individual PK data with covariates representative of patients with CAP (5000 patients/drug regimen). PTA for clinically relevant pharmacokinetic/pharmacodynamic (PK/PD) targets was calculated from steady state PK profiles for a range of minimum inhibitory concentrations (MICs). Cumulative fractions of response (CFRs) were also calculated using MIC distributions from 2012 to 2017 global surveillance data.ResultsCeftaroline fosamil (600 mg q12 h) achieved > 90% PTA at all exposure targets for each pathogen at European Committee on Antimicrobial Susceptibility Testing (EUCAST)/Clinical and Laboratory Standards Institute (CLSI) susceptibility breakpoints, and CFRs were > 99%. Ceftriaxone, but not levofloxacin, achieved 100% PTA and > 90% CFR against S. pneumoniae. Both levofloxacin and ceftriaxone achieved high PTA and CFR against H. influenzae. Levofloxacin achieved PTAs < 90% at EUCAST/CLSI breakpoints and ceftriaxone achieved PTAs < 90% at MICs up to 2 mg/L against S. aureus; both agents produced generally low CFRs against S. aureus (except levofloxacin against methicillin-sensitive S. aureus), reflecting the lack of activity of these agents against methicillin-resistant S. aureus.ConclusionCeftaroline fosamil demonstrated higher overall PTA rates than levofloxacin and ceftriaxone, in particular against S. aureus. These results provide insight regarding the potential comparative efficacy of the described antibiotics for moderate-to-severe CAP.FundingPfizer.

Potency and plasma protein binding of drugs in vitro-a potentially misleading pair for predicting in vivo efficacious concentrations in humans.

In drug discovery or preclinical stages of development, potency parameters such as IC50, Ki, or Kd in vitro have been routinely used to predict the parameters of efficacious exposure (AUC, Cmin, etc.) in humans. However, to our knowledge, the fundamental assumption that the potency in vitro is correlated with the efficacious concentration in vivo in humans has not been investigated extensively. Thus, the present review examined this assumption by comparing a wide range of published pharmacokinetic (PK) and potency data. If the drug potency in vitro and its in vivo effectiveness in humans are well correlated, the steady-state average unbound concentrations in humans [Cu_ss.avg = fu·F·Dose/(CL·τ) = fu·AUCss/τ] after treatment with approved dosage regimens should be higher than, or at least comparable to, the potency parameters assessed in vitro. We reviewed the ratios of Cu_ss.avg/potency in vitro for a total of 54 drug entities (13 major therapeutic classes) using the dosage, PK, and in vitro potency reported in the published literature. For 54 drugs, the Cu_ss.avg/in vitro potency ratios were < 1 for 38 (69%) and < 0.1 for 22 (34%) drugs. When the ratios were plotted against fu (unbound fraction), “ratio < 1” was predominant for drugs with high protein binding (90% of drugs with fu ≤ 5%; i.e., 28 of 31 drugs). Thus, predicting the in vivo efficacious unbound concentrations in humans using only in vitro potency data and fu should be avoided, especially for molecules with high protein binding.

Abstract LB-049: Low plasma levels of 13-cis-retinoic acid (isotretinoin) and its active metabolite 4-oxo-13-cis-retinoic acid are associated with lower overall survival of high-risk neuroblastoma patients

Abstract Background and purpose: Isotretinoin (13-cis-retinoic acid; 13-cisRA), a differentiation inducer, improves outcome for high-risk neuroblastoma when given after myeloablative therapy. Published pharmacokinetic (PK) studies suggested that many patients achieve 13-cisRA levels lower than 5 μM (effective against neuroblastoma in vitro) and that 4-oxo-13-cisRA is an active metabolite of 13-cisRA. We assessed the pharmacokinetics (PK) of 13-cisRA and 4-oxo-13-cisRA and their relation to treatment outcome in Children’s Oncology Group (COG) phase III studies that treated high-risk neuroblastoma patients with 13-cisRA and immunotherapy. Methods: Blood samples from COG high-risk neuroblastoma phase III clinical trials (A3973, ANBL0532, ANBL0032, and ANBL0931) were obtained for PK analyses. Plasma levels of 13-cisRA and 4-oxo-13-cisRA were measured using high-performance liquid chromatography for all patients treated with 13-cisRA. The relationship of PK to outcome was analyzed for the patient subgroup treated with 13-cisRA and ch14.18 anti-GD2 antibody + cytokines. PK variables analyzed included plasma levels of 13-cisRA, 4-oxo-13-cisRA, and the sum of both. Results: Of 617 patients, 370 (60%) achieved median plasma concentrations of 13-cisRA + 4-oxo-13-cisRA (combined) &amp;gt;5 μM. Plasma levels were higher in patients taking intact capsules relative to open-capsule takers (13-cisRA: 1.74 vs. 1.03, 4-oxo-13-cisRA: 7.2 vs. 3.3 μM, P &amp;lt; 0.001). Both 13-cisRA and 4-oxo-13-cisRA concentrations positively correlated with older age (P &amp;lt; 0.001). The relationship of PK to overall survival (OS) was analyzed for 524 patients treated with 13-cisRA and immunotherapy on ANBL0032 or ANBL0931. In patients ≥18 months old at diagnosis (n=445/524) the 5-year OS was significantly higher for patients with upper quartile 13-cisRA levels (2.5 μM, 73%) relative to lower quartile (0.6 μM, 60%, P = 0.039) although event-free survival was not significantly different (P = 0.44). Higher active metabolite concentrations (4-oxo-13-cisRA &amp;gt;5 µM, 76%) was also associated with significantly higher OS relative to lower levels (&amp;lt;1 µM, 66%, P = 0.032). Conclusions: Age and route of administration influenced plasma levels of 13-cisRA and 4-oxo-13-cisRA. Combined levels of 13-cisRA and the active metabolite (4-oxo-13-cisRA) were &amp;gt;5 µM in 85% of patients. In patients ≥18 months old, low plasma levels of 13-cisRA and 4-oxo-13-cisRA were associated with a lower overall survival. Citation Format: Hwangeui Cho, Arlene Naranjo, Collin Van Ryn, Shengping Yang, Poonam Sonawane, Judith G. Villablanca, Alice L. You, Julie R. Park, Susan Kreissman, C Patrick Reynolds, Min H. Kang. Low plasma levels of 13-cis-retinoic acid (isotretinoin) and its active metabolite 4-oxo-13-cis-retinoic acid are associated with lower overall survival of high-risk neuroblastoma patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-049. doi:10.1158/1538-7445.AM2017-LB-049

Integrated semi‐physiological pharmacokinetic model for both sunitinib and its active metabolite SU12662

Previously published pharmacokinetic (PK) models for sunitinib and its active metabolite SU12662 were based on a limited dataset or lacked important elements such as correlations between sunitinib and its metabolite. The current study aimed to develop an improved PK model that circumvented these limitations and to prove the utility of the PK model in treatment optimization in clinical practice. One thousand two hundred and five plasma samples from 70 cancer patients were collected from three PK studies with sunitinib and SU12662. A semi-physiological PK model for sunitinib and SU12662 was developed incorporating pre-systemic metabolism using non-linear mixed effects modelling (nonmem). Allometric scaling based on body weight was applied. The final model was used for simulation of the PK of different treatment regimens. Sunitinib and SU12662 PK were best described by a one and two compartment model, respectively. Introduction of pre-systemic formation of SU12662 strongly improved model fit, compared with solely systemic metabolism. The clearance of sunitinib and SU12662 was estimated at 35.7 (relative standard error (RSE) 5.7%) l h(-1) and 17.1 (RSE 7.4%) l h(-1), respectively for 70 kg patients. Correlation coefficients were estimated between inter-individual variability of both clearances, both volumes of distribution and between clearance and volume of distribution of SU12662 as 0.53, 0.48 and 0.45, respectively. Simulation of the PK model predicted correctly the ratio of patients who did not reach proposed PK targets for efficacy. A semi-physiological PK model for sunitinib and SU12662 in cancer patients was presented including pre-systemic metabolism. The model was superior to previous PK models in many aspects.

Concentration–effect relationships with perampanel in patients with pharmacoresistant partial‐onset seizures

Although there is a general paucity of published pharmacokinetic (PK) data for new antiepileptic drugs (AEDs), PK analyses of pooled data from clinical studies of perampanel have recently been presented. We present PK/pharmacodynamic (PD) analyses of pooled data from phase III studies of perampanel describing efficacy and safety as a function of exposure, in order to determine whether a predictable concentration-effect relationship exists for perampanel efficacy and/or adverse events (AEs). The effects of concomitant enzyme-inducing AEDs (EIAEDs) and non-enzyme-inducing AEDs on the exposure, efficacy, and safety of perampanel are also considered. Three multicenter, randomized, double-blind, placebo-controlled phase III studies investigated the efficacy and safety of perampanel 2-12 mg in patients with uncontrolled partial-onset seizures despite prior therapy with two or more AEDs. From baseline onward, patients also received ongoing treatment with stable doses of one to three approved concomitant AEDs. AEs were monitored throughout the studies. Changes from baseline in seizure frequency and 50% responder rates were evaluated. Exposure to perampanel was predicted based on the actual (last) dose using a previously established PK model. A population PK/PD model for the relationship between perampanel exposure and seizure frequency was estimated using nonlinear mixed-effect modeling with first-order conditional estimation, whereas logistic analyses for responder rate and AEs were performed using SAS analysis software. The PK/PD population included 1,109 patients. Seizure frequency decreased linearly as predicted perampanel average steady-state plasma concentrations increased. Concomitant EIAEDs (carbamazepine, oxcarbazepine, and phenytoin) reduced exposure to perampanel but had no effect on the slope of the PD model-predicted relationship between exposure and reduction in seizure frequency. The probability of patients achieving a response was predicted to increase as perampanel average plasma concentration at steady state increased. No demographic, AED, region, or study covariate had any effect on the probability of achieving a positive treatment response to perampanel or on the slope of the exposure-response curve. Across the phase III studies, there were reports of dizziness (32.9%), somnolence (21.7%), fatigue (13.9%), irritability (12.3%), gait disturbance (9.1%), weight increase (6.1%), dysarthria (4.5%), and euphoric mood (0.5%); the model-predicted probability of these AEs increased significantly at higher exposure to perampanel (all p < 0.001). There was no effect of demographic variables or region on the probability of experiencing any of the AEs analyzed. PK and PD analyses have played a pivotal role in the clinical development of perampanel as an adjunctive treatment for pharmacoresistant partial-onset seizures. Phase III data suggest that a significant relationship exists between increases in perampanel plasma concentration (i.e., systemic exposure) and reductions in seizure frequency. In addition, increases in perampanel plasma concentration may potentially be associated with increases in AE rates. The model-predicted concentration-safety profile of perampanel does not appear to be affected by patient age, gender, or ethnicity. Although concomitant EIAEDs may influence perampanel PK, they do not appear to alter the relationship between perampanel plasma concentration and seizure frequency. Understanding these relationships between perampanel plasma concentration and clinical response will be valuable in utilizing this novel AED.

Pharmacokinetics and Pharmacodynamics of Linezolid in Children With Cystic Fibrosis

Alternative antimicrobial regimens are needed for treatment of methicillin-resistant Staphylococcus aureus (MRSA)-associated pulmonary exacerbations in children with cystic fibrosis (CF). There are no published pharmacokinetic (PK) and pharmacodynamic (PD) data for linezolid in children with CF. (1) To determine the PK and PD profile of linezolid among children with CF; (2) to characterize the effect of linezolid on MRSA infection; (3) to determine the effect of age and CF transmembrane regulator (CFTR) gene mutations on drug clearance. Linezolid clearance is enhanced in children with CF requiring a higher dosage regimen. Age and CFTR gene mutations affect drug clearance. This was a retrospective cohort study; medical records of children with MRSA-associated pulmonary exacerbations treated with linezolid (10 mg/kg/dose IV every 8h) were reviewed. Linezolid peak and trough concentrations in serum were determined by high performance liquid chromatography, PK profiles determined using standard noncompartmental method, and PD indices were evaluated. 10 children (mean +/- SD, 10.2 +/- 5.5 years) received 14 courses of linezolid at 10 +/- 0.4 mg/kg/dose every 8h for 15.4 +/- 3.2 days. Seven had homozygous DeltaF508 CFTR mutation. Peak and trough linezolid concentrations varied widely (range, 8.4-20.5 and 0.1-11.5 mcg/mL respectively). The PK profile of children <10 years differed significantly from older patients (>or=10 years). The PK indices of children with homozygous DeltaF508 differed marginally from those with heterozygous CFTR mutations, but there were too few subjects to allow separation of age and CFTR mutations effect. No patient achieved the target PD ratio of AUC/MIC >80. MRSA persisted in sputum or throat culture after treatment with linezolid. Additional PK and PD data are needed to optimize linezolid therapy in children with cystic fibrosis; it is likely that higher doses will be needed.

Pharmacokinetics of mycophenolate mofetil are influenced by concomitant immunosuppression.

The recommended dosage for mycophenolate mofetil (MMF) in combination with cyclosporin (CyA) for pediatric kidney transplant recipients is 600 mg/m(2) twice daily (b.i.d.). We recently published pharmacokinetic (PK) profiles of MMF in combination with tacrolimus (FK506): in order to keep the mycophenolic acid (MPA) pre-dose trough concentration between 2 and 5 microg/ml and to avoid side effects, mean MMF doses were reduced to 300 mg/m(2) b.i.d. In order to investigate whether this striking difference was due to alterations of MPA clearance by CyA or FK506, we analyzed PK profiles from 13 patients who received MMF without CyA or FK506, and compared these data with 14 patients who received a combination of MMF and FK506 and 15 patients who received MMF and CyA. Mean area under the curve (AUC) in all PK profiles was 61.9+/-23.8 microgxh/ml. Although the AUCs did not differ between the groups, the dose per square meter was significantly lower in patients receiving concomitant FK506 compared with CyA, and the dose-normalized AUC was significantly higher. The MMF doses were 1,158+/-301 mg/m(2) per day in the CyA group, 555+/-289 mg/m(2) per day in the tacrolimus group, and 866+/-401 mg/m(2) per day in the group without concomitant calcineurin inhibitor treatment. The apparent clearance of MPA is reduced in combination with tacrolimus. The reason for this remains unknown. There was a trend towards lower dose-normalized AUCs in the CyA group compared with the group without calcineurin inhibitor treatment. We conclude that concomitant medication alters the clearance of MPA. It is noteworthy that there was substantial interindividual variation, despite the rather marked differences between the groups, and therefore we recommend starting MMF in combination with CyA at a dose of 600 mg/m(2) b.i.d., in combination with tacrolimus at a dose of 300 mg/m(2) b.i.d., and without a calcineurin inhibitor at a dose of 500 mg/m(2) b.i.d., and adjusting doses using therapeutic drug monitoring of MPA.