Mean Area Under The Concentration-time Curve Research Articles

Safety and Pharmacokinetics of Recombinant ADAMTS13 in Patients with Sickle Cell Disease: A Phase 1 Randomized, Double-Blind, Placebo-Controlled Study

Background Sickle cell disease (SCD) is an autosomal recessive hemoglobinopathy associated with chronic hemolysis and vaso-occlusive crises (VOCs). Despite the use of treatments such as hydroxyurea, many patients continue to experience VOCs. There is emerging evidence implicating the dysregulation of the von Willebrand factor (VWF)-ADAMTS13 axis in the pathophysiology of VOCs. The size and platelet-binding activity of ultra-large VWF multimers is regulated by the VWF-cleaving metalloprotease ADAMTS13; therefore, the administration of recombinant ADAMTS13 (rADAMTS13), particularly during VOCs, may be therapeutically beneficial in patients with SCD. Here, we present findings from a phase 1 study (NCT03997760) investigating the safety and pharmacokinetics (PK) of three doses of rADAMTS13 (TAK-755; Takeda Development Center Americas, Inc., Lexington, MA, USA) in patients with SCD. Aims To assess the safety, tolerability, and PK of 40 IU/kg, 80 IU/kg, and 160 IU/kg rADAMTS13 in patients with SCD at baseline health. Methods This phase 1, randomized, double-blind, placebo-controlled, multicenter, ascending single dose study (NCT03997760) enrolled patients aged between 18 and 65 years with a documented history of HbSS or HbSβ o thalassemia. Concurrent treatment with a stable dose of hydroxyurea was permitted. Patients were at baseline health: those diagnosed with acute VOC in the 21 days prior to dose administration were excluded. Patients who had received a blood transfusion within 30 days of screening were also excluded. Patients were randomized 3:1 to receive a single intravenous infusion of either rADAMTS13 or placebo in three sequential dose cohorts: cohort 1, 40 IU/kg; cohort 2, 80 IU/kg; cohort 3, 160 IU/kg. Patients were followed for 28 days post-infusion. Each dose cohort was opened sequentially following a review of safety data by a dose escalation committee. Primary safety endpoints included treatment-emergent adverse events (TEAEs), serious TEAEs, and the incidence of neutralizing antibodies against ADAMTS13. Secondary endpoints included an assessment of PK, comprising the maximum concentration (C max) and the area under the concentration-time curve (AUC) from zero (pre-dose) to 72 hours post-dose (AUC 0-72) estimated from ADAMTS13 antigen and activity levels, among other parameters. Results Five patients received placebo and 14 patients received a single dose of rADAMTS13 (cohort 1, n=4; cohort 2, n=6; cohort 3, n=4). The median age (range) of patients who received placebo was 36.0 (20-43) years and 2 (40.0%) were male. Median age (range) of patients who received rADAMTS13 was 38.5 (23-50) years and 9 (64.3%) were male. TEAEs were reported in 2 (40.0%) patients who received placebo and 8 (57.1%) patients who received rADAMTS13. TEAEs considered related to rADAMTS13 were reported in 4 patients (28.6%; Table). One serious TEAE (sickle cell anemia with crisis) not considered related to rADAMTS13 was reported in a patient who received 40 IU/kg rADAMTS13. No bleeding-related TEAEs were reported during the study and no TEAEs led to study discontinuation or death. No anti-ADAMTS13 neutralizing antibodies were detected within 28 days following rADAMTS13 administration. For the PK assessment, mean (standard deviation [SD]) baseline ADAMTS13 antigen was 0.68 (0.16) μg/mL, and rADAMTS13 demonstrated a dose-proportional increase in ADAMTS13 antigen level ( Figure). For cohorts 1, 2, and 3, respectively, baseline-adjusted ADAMTS13 antigen mean C max was 0.51 μg/mL (n=4), 1.07 μg/mL (n=5), and 2.08 μg/mL (n=4), and mean AUC 0-72 was 18.21 h*μg/mL (n=3), 43.01 h*μg/mL (n=5), and 74.51 h*μg/mL (n=4). Mean (SD) baseline ADAMTS13 activity was 1.06 (0.31) IU/mL. For cohorts 1, 2 and 3, respectively, mean C max for baseline-adjusted ADAMTS13 activity was 0.94 IU/mL (n=4), 2.09 IU/mL (n=5), and 3.08 IU/mL (n=4). Conclusions No safety signals or dose-limiting toxicities, such as bleeding events, were observed for the three evaluated doses of rADAMTS13 up to 160 IU/kg, and no rADAMTS13-related serious TEAEs were reported. No anti-ADAMTS13 neutralizing antibodies were detected during the study. rADAMTS13 demonstrated a dose-proportional increase in ADAMTS13 antigen levels, which is consistent with linear PK. Findings from this study support the further investigation of rADAMTS13 as a potential therapeutic option for patients with SCD.

A Phase 1, Multicenter, Open-Label Study to Evaluate the Pharmacokinetics of Iberdomide in Subjects with Mild, Moderate, or Severe Hepatic Impairment Compared with Healthy Subjects.

Iberdomide, a novel cereblon modulator (CELMoD®), is currently under clinical investigation for hematology indications. To evaluate the influence of hepatic impairment on the pharmacokinetics (PK) of iberdomide and its major active metabolite M12, a phase 1, multicenter, open-label study was conducted in healthy subjects and subjects with mild, moderate, and severe hepatic impairment. Forty subjects were enrolled in the study and divided into five groups based on hepatic function. 1 mg iberdomide was administered and plasma samples were collected to evaluate the pharmacokinetics of iberdomide and M12. After a single dose of iberdomide (1 mg), mean iberdomide Cmax (maximum observed concentration) and AUC (area under the concentration-time curve) exposure were generally comparable between hepatic impairment (HI) subjects (severe, moderate and mild) and their respective matched normal controls. Mean Cmax and AUC exposure of the metabolite M12 were generally comparable between mild HI and matched normal subjects. However, mean Cmax of the M12 was 30% and 65% lower and AUC was 57% and 63% lower in moderate and severe HI subjects as compared to their respective matched normal controls. However, given the relatively low M12 exposure as compared to its parent drug, the observed differences were not considered clinically meaningful. In summary, 1 mg single oral dose of iberdomide was generally well-tolerated. HI (mild, moderate or severe) had no clinically relevant impact on iberdomide PK and therefore, no dose adjustment is warranted.

PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSIS OF AMISELIMOD, A SELECTIVE SPHINGOSINE 1-PHOSPHATE RECEPTOR MODULATOR, IN HEALTHY SUBJECTS: RESULTS FROM A PHASE 1 STUDY

Abstract BACKGROUND Amiselimod is a selective sphingosine 1-phosphate receptor modulator in development for inflammatory bowel disease. It is converted to its active metabolite, amiselimod phosphate (amiselimod-P), and has a long half-life and slow accumulation to steady state. We evaluated a multiple-dose titration regimen to determine the plasma pharmacokinetic (PK) profile of amiselimod and amiselimod-P at steady state for the 0.4 mg QD therapeutic dose on day 13 and for the 0.8 mg QD supratherapeutic dose on day 26. We also investigated the pharmacodynamic (PD) effect of amiselimod on absolute lymphocyte counts (ALCs). METHODS A randomized, double-blind, multiple-dose, placebo-controlled, parallel study with a nested crossover design assessed amiselimod and amiselimod-P. Healthy adults received a single dose of placebo followed by oral amiselimod, which was upwardly titrated in doses ranging from 0.4 to 1.6 mg QD to rapidly achieve steady-state concentrations for the 0.4 mg QD and 0.8 mg QD doses within a 28-day treatment period. The PK parameters of amiselimod and amiselimod-P (on days 1, 13 and 26) included the geometric mean (geometric coefficient of variation percentage [CV%]) maximum plasma concentration (Cmax), median (minimum, maximum) time to Cmax (Tmax), geometric mean (geometric CV%) area under the concentration-time curve (AUC) from time 0 to the last measurable concentration, and geometric mean (geometric CV%) AUC from time 0 to 23.5 hours postdose (AUC0-23.5). Multidose PD were evaluated by changes in ALCs. RESULTS The PK population included 95 amiselimod-treated participants and the PD population included 190 participants who received amiselimod or placebo. On day 13, the steady-state AUC and Cmax for amiselimod 0.4 mg QD increased by 10-fold for amiselimod and by 4-fold for amiselimod-P compared with day 1. On day 26, the steady-state AUC0-23.5 and Cmax for amiselimod 0.8 mg QD increased by 1.9-fold for amiselimod and by 1.8-fold for amiselimod-P compared with day 13. The median Tmax of plasma amiselimod and amiselimod-P were similar on all 3 days and were reached at 11 to 12 hours postdose for amiselimod and at 10 hours postdose for amiselimod-P. The mean ALCs for amiselimod exhibited a gradual decrease from predose (1.681 × 103/uL) to a nadir of 0.424 × 103/uL on day 27. CONCLUSIONS The abbreviated amiselimod dosing titration regimen reached steady state within 14 days for the therapeutic 0.4 mg QD regimen and within 26 days for the supratherapeutic 0.8 mg QD regimen; expected decreases in ALCs were observed following amiselimod.

Evaluation of Limited Sampling Strategies for Bayesian Estimation of Daptomycin Area Under the Concentration-Time Curve: A Short Communication.

Increasing evidence supports daptomycin therapeutic drug monitoring. The author's reference center used to perform therapeutic drug monitoring in patients who receive high-dose daptomycin for bone and joint infections, with a three-sample strategy to estimate the daptomycin daily area under the concentration-time curve (AUC). The objective of this study was to evaluate simpler strategies based on only 2 or 1 sample(s). The authors used the BestDose software to estimate the daptomycin AUC after Bayesian posterior estimation of individual pharmacokinetic (PK) parameters at steady state. The reference AUC (AUC full ) was based on 3 samples obtained predose (T0) and approximately 1 hour (T1) and 6 hours (T6) after the start of a 30-minute infusion of IV daptomycin. It was compared with the AUC based on all possible 2-sample and 1-sample strategies. Bias, imprecision, regression, and Bland-Altman plots were used to assess the performance of the alternative strategies. Data from 77 patients were analyzed. The mean AUC full value was 936 ± 373 mg·h/L. The best 2-sample strategy was T0 + T6, with a mean prediction bias of 0.13 mg·h/L and absolute imprecision of 3%. The T0 + T1 strategy also performed well with a mean bias of -10 mg·h/L and imprecision of 3%. The best 1-sample strategy was the T6 sample only with a bias of 2.19 mg·h/L and imprecision of 6%. Bayesian estimation of daptomycin AUC based on a two-sample strategy was associated with negligible bias and imprecision compared with the author's usual three-sample strategy. The trough and peak strategy may shorten and simplify patient visits and reduce assay labor and costs.

Pharmacokinetics and tolerability of the dual TORC1/2 inhibitor sapanisertib in combination with the MEK inhibitor trametinib in dogs.

Activation of one or both the Ras/MAPK and PI3K/Akt/mTOR signal transduction pathways are known to mediate oncogenicity of several canine and human cancers, including mucosal melanomas. Reciprocal cross activation between the two pathways can be a source of drug resistance. Consequently, oral dosing for plasma pharmacokinetic (PK) analysis and tolerability to a combination of sapanisertib, a dual TORC1/2 inhibitor, and trametinib, a MEK inhibitor, was evaluated in nontumor-bearing laboratory dogs for its potential application in parallel pathway targeting. Twelve dogs, divided into three equal cohorts, received either the combination or single agents. Animals were monitored for PK following single dose and 17-day repeat dosing, and by clinical observations, hematology, serum biochemistry, coagulation studies and urinalyses. A single trametinib dose (0.025 mg/kg), sulfated as dimethyl sulfoxide which enhanced its absorption, reached mean maximum concentration (Cmax) 0.64 ng/mL [18% coefficient of variation (CV)] at a median time to maximum concentration (Tmax) of 1.5 h (hr), and mean area under the concentration-time curve (AUC) 16.8 hr*ng/mL (14%CV), which were similar when given alone or in combination with sapanisertib. A prolonged half-life afforded 3-4-fold plasma accumulation of trametinib with daily dosing, analogous to humans. Trametinib PK mirrored previous regulatory data in dogs, while exposure approximated some published human values but generally not all patients. Sapanisertib-alone in canine plasma following single 0.1 mg/kg dose [mean Cmax 26.3 ng/mL (21%CV), median Tmax 2.0 hr, and mean AUC 248 hr*ng/mL (41%CV)] resembled levels in human therapeutic trials; whereas canine sapanisertib exposure was reduced when combined with trametinib, a known cytochrome P450 CYP3A4 inducer. Sex differences were not observed for either drug. Side effects upon repeat dosing with either or both drugs may include body weight loss, maldigestion, and cutaneous discoloration. The combination was tolerated without dose limiting toxicity, although clinical laboratory analyses revealed drug-induced acute-phase inflammation, proteinuria, and decreased blood reticulocytes, mild changes not necessitating intervention. Short-term results in dogs with this combination would appear to hold translational promise for clinical trial evaluation to target canine and possibly human melanoma, as well as other cancers having one or both signal transduction pathway activations.

P029 Pharmacokinetic/Pharmacodynamic Analysis of Amiselimod, a Selective Sphingosine 1-Phosphate Receptor Modulator, in Healthy Subjects: Results From a Phase 1 Study.

Amiselimod is a selective sphingosine 1-phosphate receptor modulator in development for inflammatory bowel disease. It is converted to its active metabolite, amiselimod phosphate (amiselimod-P), and has a long half-life and slow accumulation to steady state. We evaluated a multiple-dose titration regimen to determine the plasma pharmacokinetic (PK) profile of amiselimod and amiselimod-P at steady state for the 0.4 mg QD therapeutic dose on day 13 and for the 0.8 mg QD supratherapeutic dose on day 26. We also investigated the pharmacodynamic (PD) effect of amiselimod on absolute lymphocyte counts (ALCs). A randomized, double-blind, multiple-dose, placebo-controlled, parallel study with a nested crossover design assessed amiselimod and amiselimod-P. Healthy adults received a single dose of placebo followed by oral amiselimod, which was upwardly titrated in doses ranging from 0.4 to 1.6 mg QD to rapidly achieve steady-state concentrations for the 0.4 mg QD and 0.8 mg QD doses within a 28-day treatment period. The PK parameters of amiselimod and amiselimod-P (on days 1, 13 and 26) included the geometric mean (geometric coefficient of variation percentage [CV%]) maximum plasma concentration (Cmax), median (minimum, maximum) time to Cmax (Tmax), geometric mean (geometric CV%) area under the concentration-time curve (AUC) from time 0 to the last measurable concentration, and geometric mean (geometric CV%) AUC from time 0 to 23.5 hours post dose (AUC0-23.5). Multidose PD were evaluated by changes in ALCs. The PK population included 95 amiselimod-treated participants and the PD population included 190 participants who received amiselimod or placebo. On day 13, the steady-state AUC and Cmax for amiselimod 0.4 mg QD increased by 10-fold for amiselimod and by 4-fold for amiselimod-P compared with day 1. On day 26, the steady-state AUC0-23.5 and Cmax for amiselimod 0.8 mg QD increased by 1.9-fold for amiselimod and by 1.8-fold for amiselimod-P compared with day 13. The median Tmax of plasma amiselimod and amiselimod-P were similar on all 3 days and were reached at 11 to 12 hours post dose for amiselimod and at 10 hours post dose for amiselimod-P. The mean ALCs for amiselimod exhibited a gradual decrease from pre-dose (1.681 × 103/uL) to a nadir of 0.424 × 103/uL on day 27. The abbreviated amiselimod dosing titration regimen reached steady state within 14 days for the therapeutic 0.4 mg QD regimen and within 26 days for the supratherapeutic 0.8 mg QD regimen; expected decreases in ALCs were observed following amiselimod.

Pharmacokinetics of Oral Formulations of Gepotidacin (GSK2140944), a Triazaacenaphthylene Bacterial Type II Topoisomerase Inhibitor, in Healthy Adult and Adolescent Participants.

ABSTRACTGepotidacin is a novel, first-in-class triazaacenaphthylene antibiotic that may provide a new treatment option for antibiotic-resistant pathogens. Two pharmacokinetic evaluations of oral gepotidacin are presented: a relative bioavailability study that guided formulation development, followed by an adult and adolescent study of the final formulation. In the relative bioavailability study, after gepotidacin administration to 26 healthy adults as free-base roller-compacted (RC) tablets, free-base high-shear wet granulation (HSWG) tablets, and mesylate salt reference capsules, the RC tablet exposure ratios and 90% confidence intervals (CIs) were within the 0.80-to-1.25 confidence bounds; however, the HSWG tablet maximum observed concentration (Cmax) was higher than the reference (ratio, 1.15; 90% CI, 1.0113, 1.3047). In the healthy adult (n = 16) and adolescent (n = 17) study, a gepotidacin mesylate salt tablet was evaluated as a 1,500-mg single dose or 2 doses administered 6 or 12 h apart (6,000 mg total), or placebo was administered. The single-dose mean Cmax was ∼27% higher in adolescents than in adults, and area under the concentration-time curve (AUC) values were comparable in both populations. After 2 doses were administered, the mean Cmax values were similar for both age groups, and the mean AUC was ∼35% higher in adolescents than in adults. Concentrations increased proportionally with dose. Safety-risk profiles were similar for both age groups. Across studies, the most common adverse events were gastrointestinal. Overall, the pharmacokinetics of the final gepotidacin mesylate salt tablet have been well characterized, enrollment of adolescents into the pivotal trials is supported, and dosing intervals were determined that should provide adequate exposures for microbiological efficacy. (This study has been registered at ClinicalTrials.gov under identifiers NCT02853435 and NCT04079790.)

Busulfan Pharmacogenetics and Drug Exposure in Cancer Patients Undergoing Hematopoietic Stem Cell Transplantation

Introduction: Busulfan, a bifunctional alkylating agent widely used in conditioning regimens before hematopoietic stem cell transplantation (HSCT), is metabolized via glutathione-S-transferases (GSTs) and cytochrome P450 (CYP) enzymes. Busulfan demonstrates wide interpatient variability in pharmacokinetics (PK); high drug exposure is associated with increased risk of toxicities (e.g. veno-occlusive disease) and low drug exposure is associated with increased risk of relapse and graft failure. Drug exposure within a narrow therapeutic range yields optimal results. PK-guided dosing is used in many patients to achieve optimal drug exposure; however, better methods to select the initial dose would improve consistency of busulfan exposure and the likelihood of achieving the target area under the concentration-time curve (AUC). Previous pharmacogenomic (PGx) studies have identified GST polymorphisms as predictors of drug exposure, however, these were primarily performed in pediatric populations and/or Asians. We performed a PGx study in adult HSCT patients to identify polymorphisms in candidate genes associated with busulfan AUC and clearance.Methods: Buccal swabs were collected from HSCT patients scheduled to receive busulfan as part of their conditioning regimen on the day of admission (one day prior to initiating busulfan) between 04/28/14 and 06/06/2017. DNA was extracted using the GenElute™ Mammalian Genomic DNA Kit. A custom Ion AmpliSeq™ PGx Panel and various orthogonal methods were used to genotype the samples for polymorphisms in GSTA1 (135T>C), GSTM1 (null/present), GSTP1 (Ile105Val, Ala114Val), CYP2B6 (*2, *4, *5, *6, *18, *22), CYP2C8 (*2, *3), CYP2C9 (*2, *3, *8, *11), CYP2C19 (*2, *3, *17), and MTHFR (A1298C, C677T). Phenotypes were inferred according to established guidelines or literature. IV busulfan was administered once daily over 3 hours at 2.8 mg/kg (for autos) or 3.2 mg/kg (for allos) for a total of 4 doses. PK samples were obtained at 15 mins, 1 hr, 2 hrs, 3 hrs, and 5 hrs after the end of the first infusion. Non-compartmental analysis was performed to estimate PK parameters and doses 3 and 4 were adjusted to target an AUC of either 4500 or 5000 uM*min/L, depending on transplant type and conditioning regimen. The primary objective was to investigate the impact of polymorphisms on busulfan AUC, which was measured using univariate linear regression analysis adjusting for dose. Secondary objectives included a comparison of mean AUCs between phenotypes, which was measured using ANOVA, and to determine the association between SNPs and busulfan clearance using univariate linear regression adjusting for dose.Results: A total of 36 patients were evaluable for the primary endpoint. The median age was 47 (22-73) years, 56% were male, 75% received busulfan/cyclophosphamide/etoposide, 22% received busulfan/cyclophosphamide with post-transplant cyclophosphamide, and 3% received thiotepa/busulfan/cyclophosphamide. The genotype and inferred phenotype frequencies are summarized in Table 1. The mean AUC across all patients was 4255 µM*min/L (range 2834-5989). Results from the univariate linear regression analysis identified that CYP2B6 polymorphisms were significantly associated with busulfan AUC (intermediate [IM] vs. poor metabolizer [PM], p = 0.05; normal/rapid metabolizer [NM/RM] vs. PM, p = 0.02) (Table 2). The mean AUC in CYP2B6 PMs, IMs, NM/RMs was 5242, 4277, and 4134 µM*min/L, respectively (p = 0.03 by ANOVA test). There was no association of polymorphisms in GSTA1, GSTM1, GSTP1, CYP2C8, CYP2C9, CYP2C19 and MTHFR with AUC. CYP2B6 polymorphisms were also associated with busulfan clearance (IM vs. PM, p = 0.07; NM/RM vs. PM, p = 0.03).Conclusion: CYP2B6 polymorphisms were significantly associated with busulfan AUC and clearance; these appear to be an important determinant of drug exposure, however, GST polymorphisms did not replicate as significant, possibly due to differences in patient populations. PGx testing for CYP2B6 may provide an important tool to individualize up front dosing and improve the likelihood of achieving the target AUC earlier or to achieve target AUC in a higher proportion of the many patients who do not receive PK-guided dosing; however, our findings require further validation in larger cohorts of patients. We plan to enroll more patients and assess the relationship between PK, PGx and clinical outcomes, including toxicity and response. [Display omitted] DisclosuresTrivedi:Pharmacyclics: Consultancy, Honoraria. Grunwald:Pfizer: Consultancy; Alexion: Consultancy; Incyte: Consultancy, Research Funding; Genentech: Research Funding; Celgene: Consultancy; Amgen: Consultancy, Research Funding; ARIAD: Consultancy; Cardinal Health: Consultancy; Forma Therapeutics: Research Funding; Janssen: Research Funding. Ghosh:AbbVie: Consultancy, Honoraria, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding, Speakers Bureau; Jassen: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Kite Pharma: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; TG Therapeutics: Consultancy, Honoraria, Research Funding.

Development of a limited sampling strategy for the estimation of isoniazid exposure considering N-acetyltransferase 2 genotypes in Korean patients with tuberculosis

A limited sampling strategy (LSS) to estimate the exposure to isoniazid was developed considering N-acetyltransferase 2 (NAT2) genotypes in Korean patients with tuberculosis. The influence of the genotypes on the pharmacokinetics of isoniazid was also evaluated. A total of 33 participants participated in the study and received isoniazid 300 mg once daily. Evaluable participants consist of ten slow (SA), fourteen intermediate (IA) and six rapid acetylators (RA). As expected, isoniazid exposure was higher (mean AUC, 28.4 versus 7.6 mg*h/L) and systemic clearance lower (mean apparent clearance, 14.8 versus 50.6 L/h) in SAs than RAs. The formulas to estimate isoniazid exposure were constructed using one or more concentration-time points that correlate with the area under the concentration-time curve (AUC). The LSS using a formula of single concentration-time point at 4 h post dose (C4) is applicable for all acetylators to the therapeutic drug monitoring (TDM) of isoniazid in patients with tuberculosis when evaluated using the Deming regression and Bland-Altman plot (AUC = 1.53 + 10.03*C4, adjusted r2 = 0.95, p < 0.001). Considering that SAs are more prone to adverse effects, pre-dose NAT2 genotyping would be valuable for optimal isoniazid dosing in conjunction with TDM.

Modulation of CYP3A Activity to Increase the Oral Bioavailability of Ibrutinib

BackgroundIbrutinib (Imbruvica; PCI‐32765), an orally administered inhibitor of Bruton’s tyrosine kinase, is considered a breakthrough targeted therapy that is approved as frontline therapy in chronic lymphocytic leukemia (CLL). Ibrutinib has an average oral bioavailability in humans of &lt;4% with substantial variability in exposure, which predisposes patients to unpredictable and potentially harmful adverse events such as bleeding and atrial fibrillation. As ibrutinib is subject to extensive first‐pass metabolism by CYP3A following oral administration, inhibition of CYP3A activity may be a promising strategy to increase the bioavailability and decrease inter‐individual pharmacokinetic (PK) variability of ibrutinib. The objective of this study was to characterize the impact of CYP3A on the PK of ibrutinib and its main active metabolite, PCI‐45227, in mice.MethodsTo characterize the impact of CYP3A on ibrutinib disposition, in vivo PK studies were performed in wild‐type (WT) male and female FVB mice treated with CYP3A inhibitors including ketoconazole (50 mg/kg p.o.) and cobicistat (30 mg/kg; p.o.) or the respective vehicle controls (PEG400 or corn oil p.o.) thirty minutes prior to dosing with ibrutinib (10 mg/kg p.o.). Based on these results, CYP3A(−/−) female FVB mice were treated with ibrutinib (10 mg/kg p.o. or 1 mg/kg i.v.) alone or thirty minutes after administration of cobicistat (30 mg/kg; p.o.). Concentrations of ibrutinib and PCI‐45227 in plasma were determined by a validated method based on liquid chromatography‐tandem mass spectrometry, and PK parameter estimates were calculated with the software package Phoenix WinNonlin (Version 8.1). Student t‐tests comparing mean AUC values between groups were used to determine significance.ResultsThe peak plasma concentration (Cmax) and area under the concentration‐time curve (AUC) of ibrutinib were ~10‐fold higher in mice administered pharmacologic CYP3A inhibitors prior to ibrutinib (P &lt; 0.0001) with a substantial decrease in the PCI‐45227 to ibrutinib AUC ratio. As expected, when ibrutinib was administered orally to CYP3A(−/−) mice, the AUC of ibrutinib in CYP3A(−/−) mice was increased ~10‐fold (P &lt; 0.0001) with almost no formation of the PCI‐45227 metabolite compared with WT mice. Cobicistat did not impact ibrutinib AUC in CYP3A(−/−) mice (P &gt; 0.9), which suggests that CYP3A inhibition is the major mechanism for cobicistat‐induced increases in ibrutinib exposure.ConclusionsPreviously obtained data with other kinase inhibitors indicate that patients with high CYP3A4 activity may benefit from an increased dose to achieve drug concentrations required to interact with kinase targets; a strategy by which enzyme activity is inhibited could achieve similar results. In view of the established inverse‐correlation between absolute bioavailability and inter‐individual PK variability, the current data provide a rationale for the development of exploratory clinical studies aimed at decreasing the variability in ibrutinib exposure by concomitant administration of CYP3A4 inhibitors. Future preclinical efficacy studies will determine the impact of this strategy on survival in mouse models of B‐cell malignancies.

Racial difference in bioavailability of oral ibandronate between Caucasian and Taiwanese postmenopausal women.

Interethnic differences in the pharmacokinetics of oral ibandronate for osteoporosis are unknown. We compared the disposition of oral ibandronate between Caucasian and Taiwanese postmenopausal women. Ibandronate 150mg was administered to 35 Caucasian and 16 Taiwanese postmenopausal women in two separate phase 1 studies. Interethnic comparisons were performed to assess pharmacokinetic properties, including the area under the concentration-time curve (AUC), peak concentration (Cmax), elimination half-life, urinary drug recovery (Ae%), renal clearance (CLr), apparent total clearance (CL/F), and apparent volume of distribution (Vd/F). The mean AUC, Cmax, and Ae% were 2.41-, 1.69-, and 2.95-fold greater in the Taiwanese than in the Caucasian subjects, and the average CL/F and Vd/F were 2.48- and 2.46-fold smaller. There were no significant differences in mean CLr and half-life between both groups. As bisphosphonates are not biotransformed but are mainly excreted in the urine, the total body clearance is close to the CLr. These results suggested a larger bioavailability in the Taiwanese group which resulted in the differences in the CL/F and Vd/F. Multiple linear regression analysis demonstrated ethnicity influences of the pharmacokinetic properties after adjusting for the other variables. Bioavailability was largely responsible for the interethnic pharmacokinetic differences following oral administration of 150mg ibandronate and seemed greater in the Taiwanese compared with the Caucasian subjects. Further dose-ranging studies are warranted to determine the optimal dosages of oral ibandronate in patients of Asian or Taiwanese ethnicity.

1561. Omadacycline Pharmacokinetics: Influence of Mortality Risk Score Among Patients with Community-Acquired Bacterial Pneumonia

BackgroundOmadacycline is a novel aminomethylcycline with activity against Gram-positive and -negative organisms, including tetracycline-resistant pathogens. Omadacycline was recently approved in the United States for treatment of adult patients with community-acquired bacterial pneumonia (CABP) and acute bacterial skin and skin structure infections. Analyses were undertaken to determine whether PORT risk class and CURB-65 score influence the pharmacokinetics of omadacycline in patients with CABP.MethodsOmadacycline pharmacokinetic data were available from omadacycline-treated patients with CABP enrolled in the Phase 3 OPTIC Study. Patients received omadacycline 100 mg IV q12h on Day 1 followed by 100 mg IV q24h. After Day 3, patients could be switched to 300 mg PO q24h if predefined clinical stability criteria were met. Four pharmacokinetic samples per patient were collected between Days 2 and 5. These data were previously utilized in the development of a population pharmacokinetic model describing the disposition of omadacycline [Microbe 2018; Abstr SAT-628]. Individual post-hoc parameter estimates for patients enrolled in the OPTIC study were utilized to compute Day 1 total-drug plasma area under the concentration-time curve (AUC) values following administration of omadacycline 100 mg IV q12h. Differences among these AUC values by PORT risk class and CURB-65 score were assessed using a one-way ANOVA.ResultsA total of 187 pharmacokinetic samples were available from 50 patients. Among the patients classified as PORT risk class II, III, and IV (n = 12, 28, and 10, respectively), mean Day 1 omadacycline AUC values were 10.2, 11.0, and 12.0 mg L/h, respectively. Among patients with CURB-65 scores of 0, 1, and 2 (n = 23, 23, and 4, respectively), mean Day 1 omadacycline AUC values were 10.6, 11.6, and 9.7 mg L/h, respectively. The differences in mean AUC values were not statistically significant among patients by PORT risk class (P = 0.248) and CURB-65 score groups (P = 0.745). Moreover, variability was similar across these groups as displayed in Figure 1.ConclusionOmadacycline exposures were similar across PORT risk class and CURB-65 score groups; thus, omadacycline dose adjustments based on these classifications are likely not warranted. Disclosures All authors: No reported disclosures.

Exploring the Use of C-Reactive Protein to Estimate the Pharmacodynamics of Vancomycin.

C-reactive protein (CRP) pharmacodynamic (PD) models have the potential to provide adjunctive methods for predicting the individual exposure response to antimicrobial therapy. We investigated CRP PD linked to a vancomycin pharmacokinetic (PK) model using routinely collected data from noncritical care adults in secondary care. Patients receiving intermittent intravenous vancomycin therapy in secondary care were identified. A 2-compartment vancomycin PK model was linked to a previously described PD model describing CRP response. PK and PD parameters were estimated using a Non-Parametric Adaptive Grid technique. Exposure-response relationships were explored with vancomycin area-under-the-concentration-time-curve (AUC) and EC50 (concentration of drug that causes a half maximal effect) using the index, AUC:EC50, fitted to CRP data using a sigmoidal Emax model. Twenty-nine individuals were included. Median age was 62 (21-97) years. Fifteen (52%) patients were microbiology confirmed. PK and PD models were adequately fitted (r 0.83 and 0.82, respectively). There was a wide variation observed in individual Bayesian posterior EC50 estimates (6.95-48.55 mg/L), with mean (SD) AUC:EC50 of 31.46 (29.22). AUC:EC50 was fitted to terminal CRP with AUC:EC50 >19 associated with lower CRP value at 96-120 hours of therapy (100 mg/L versus 44 mg/L; P < 0.01). The use of AUC:EC50 has the potential to provide in vivo organism and host response data as an adjunct for in vitro minimum inhibitory concentration data, which is currently used as the gold standard PD index for vancomycin therapy. This index can be estimated using routinely collected clinical data. Future work must investigate the role of AUC:EC50 in a prospective cohort and explore linkage with direct patient outcomes.

Dosing and Pharmacokinetics of Polymyxin B in Patients with Renal Insufficiency.

Polymyxin B remains the last-line treatment option for multidrug-resistant Gram-negative bacterial infections. Current U.S. Food and Drug Administration-approved prescribing information recommends that polymyxin B dosing should be adjusted according to the patient's renal function, despite studies that have shown poor correlation between creatinine and polymyxin B clearance. The objective of the present study was to determine whether steady-state polymyxin B exposures in patients with normal renal function were different from those in patients with renal insufficiency. Nineteen adult patients who received intravenous polymyxin B (1.5 to 2.5 mg/kg [actual body weight] daily) were included. To measure polymyxin B concentrations, serial blood samples were obtained from each patient after receiving polymyxin B for at least 48 h. The primary outcome was polymyxin B exposure at steady state, as reflected by the area under the concentration-time curve (AUC) over 24 h. Five patients had normal renal function (estimated creatinine clearance [CLCR] ≥ 80 ml/min) at baseline, whereas 14 had renal insufficiency (CLCR < 80 ml/min). The mean AUC of polymyxin B ± the standard deviation in the normal renal function cohort was 63.5 ± 16.6 mg·h/liter compared to 56.0 ± 17.5 mg·h/liter in the renal insufficiency cohort (P = 0.42). Adjusting the AUC for the daily dose (in mg/kg of actual body weight) did not result in a significant difference (28.6 ± 7.0 mg·h/liter versus 29.7 ± 11.2 mg·h/liter, P = 0.80). Polymyxin B exposures in patients with normal and impaired renal function after receiving standard dosing of polymyxin B were comparable. Polymyxin B dosing adjustment in patients with renal insufficiency should be reexamined.

Bayesian Estimation of Tobramycin Exposure in Patients with Cystic Fibrosis.

Fixed tobramycin (mg/kg) dosing is often inappropriate in patients with cystic fibrosis (CF), as pharmacokinetics are highly variable. The area under the concentration-time curve (AUC) is an exposure metric suited to monitoring in this population. Bayesian strategies to estimate AUC have been available for over 20 years but are not standard practice in the clinical setting. To assess their suitability for use in clinical practice, three AUC estimation methods using limited sampling were compared to measured true exposure by using intensive sampling tobramycin data. Adults prescribed once daily intravenous tobramycin had eight concentrations taken over 24 h. An estimate of true exposure within one dosing interval was calculated using the trapezoidal method and compared to three alternate estimates determined using (i) a two-sample log-linear regression (LLR) method (local hospital practice); (ii) a Bayesian estimate using one concentration (AUC1); and (iii) a Bayesian estimate using two concentrations (AUC2). Each method was evaluated against the true measured exposure by a Bland-Altman analysis. Twelve patients with a median (range) age and weight of 25 (18 to 36) years and 66.5 (51 to 76) kg, respectively, were recruited. There was good agreement between the true exposure and the three alternate estimates of AUC, with a mean AUC bias of <10 mg/liter · h in each case, i.e., -8.2 (LLR), 3.8 (AUC1), and 1.0 (AUC2). Bayesian analysis-based and LLR estimation methods of tobramycin AUC are equivalent to true exposure estimation. All three methods may be suitable for use in the clinical setting; however, a one-sample Bayesian method may be most useful in ambulatory patients for which coordinating blood samples is difficult. Suitably powered, randomized clinical trials are required to assess patient outcomes.

Development of a pharmacokinetic-guided dose individualization strategy for hydroxyurea treatment in children with sickle cell anaemia.

Hydroxyurea has emerged as the primary disease-modifying therapy for patients with sickle cell anaemia (SCA). The laboratory and clinical benefits of hydroxyurea are optimal at maximum tolerated dose (MTD), but the current empirical dose escalation process often takes up to 12months. The purpose of this study was to develop a pharmacokinetic-guided dosing strategy to reduce the time required to reach hydroxyurea MTD in children with SCA. Pharmacokinetic (PK) data from the HUSTLE trial (NCT00305175) were used to develop a population PK model using non-linear mixed effects modelling (nonmem 7.2). A D-optimal sampling strategy was developed to estimate individual PK and hydroxyurea exposure (area under the concentration-time curve (AUC)). The initial AUC target was derived from HUSTLE clinical data and defined as the mean AUC at MTD. PK profiles were best described by a one compartment with Michaelis-Menten elimination and a transit absorption model. Body weight and cystatin C were identified as significant predictors of hydroxyurea clearance. The following clinically feasible sampling times are included in a new prospective protocol: pre-dose (baseline), 15-20min, 50-60min and 3h after an initial 20mgkg(-1) oral dose. The mean target AUC(0,∞) for initial dose titration was 115mgl(-1) h. We developed a PK model-based individualized dosing strategy for the prospective Therapeutic Response Evaluation and Adherence Trial (TREAT, ClinicalTrials.gov NCT02286154). This approach has the potential to optimize the dose titration of hydroxyurea therapy for children with SCA, such that the clinical benefits at MTD are achieved more quickly.

Quantifying the Effectiveness of Dose Individualization by Simulation for a Drug With Moderate Pharmacokinetic Variability.

Dose individualization can reduce variability in exposure. The objective of this work was to quantify, through pharmacokinetic (PK) simulation, the potential for reducing the variability in exposure by dose individualization for a drug with moderate PK variability between subjects and between occasions within a subject, and a narrow therapeutic window. Using a population PK model that includes between-subject and between-occasion variability for apparent clearance, individual PK profiles in a trial of 300 subjects after a test dose were simulated. From the simulated data, datasets were created mimicking various sampling regimens (from single predose sample to full profile samples over 12 hours) on 1 or more occasions (1, 2, 3, 5, or 10 visits). Using these datasets, individual apparent clearance values were estimated, which were then used to calculate an individualized dose for a predefined target area under the concentration-time curve (AUC), based on the available formulation strengths. The proportion of people whose mean AUC was within a predefined therapeutic AUC range was calculated for the test (before) and the individualized dose (after), and compared between the different sampling scenarios. The maximum increase in proportion of subjects with an AUC within the range was 20%. To achieve this benefit, PK samples over 4 hours from 100 dosing occasions were required. As a result of the dose adjustment, the AUC of 7.3% of the subjects moved from inside the therapeutic range to outside of the range. This work shows how modeling and simulation can help assess the benefit and risk of dose individualization for a compound with variability between subjects and between occasions. The framework can be applied to similar situations with a defined set of conditions (eg, therapeutic window, tablet strengths, and PK and/or pharmacodynamic sampling scheme) to inform dose change and to assess the utility of dose individualization against certain success criteria.

Proximal Roux-en-Y gastric bypass alters drug absorption pattern but not systemic exposure of CYP3A4 and P-glycoprotein substrates.

To evaluate the effect of Roux-en-Y gastric bypass surgery (RYGB) on the pharmacokinetics of midazolam (a CYP3A4 substrate) and digoxin (a P-glycoprotein substrate). Prospective, nonblinded, longitudinal, single-dose pharmacokinetic study in three phases: presurgery baseline and postoperative assessments at 3 and 12months. Twelve obese patients meeting current standards for bariatric surgery. At each study visit, patients received a single dose of oral digoxin and midazolam at 8a.m. Blood samples were collected at regular intervals for 24hours after dosing. Continuous 12-lead electrocardiogram (EKG), heart rate, blood pressure, and respiratory rate were monitored, and pharmacokinetic parameters from the three visits were compared. The peak plasma concentration (Cmax ) of midazolam increased by 66% and 71% at 3- and 12-month post-RYGB (p=0.017 and p=0.001, respectively), whereas the median time to peak concentration (Tmax ) was reduced by 50%. The mean Cmax for 1'-hydroxymidazolam increased by 87% and 80% at 3 and 12 months (p=0.001 and p<0.001, respectively). However, neither the area under the concentration-time curve (AUC) for midazolam nor the metabolite-to-parent AUC ratio changed significantly over time. For digoxin, the median Tmax decreased from 40minutes at baseline to 30 and 20minutes at 3 and 12 months, respectively. The mean AUC for digoxin, heart rate, and EKG patterns were similar across the three study phases. Contemporary proximal RYGB increases the rate of drug absorption without significantly changing the overall exposure to midazolam and digoxin. The Cmax of a CYP3A4 substrate with a high extraction ratio was substantially increased after RYGB.

Assessing Pharmacokinetics of Different Doses of Fosfomycin in Laboratory Rats Enables Adequate Exposure for Pharmacodynamic Models

Fosfomycin has been the subject of numerous pharmacodynamic in vivo models in recent years. The present study set out to determine fosfomycin pharmacokinetics in laboratory rats to enable adequate dosing regimens in future rodent models. Fosfomycin was given intraperitoneally as single doses of 75, 200 and 500 mg/kg bodyweight to 4 Sprague-Dawley rats per dose group. Blood samples were collected over 8 h and fosfomycin concentrations were determined by HPLC-mass spectrometry. Fosfomycin showed a dose-proportional pharmacokinetic profile indicated by a correlation of 0.99 for maximum concentration and area under the concentration-time curve (AUC). The mean AUC_0-8 after intraperitoneal administration of 75, 200 or 500 mg/kg bodyweight fosfomycin were 109.4, 387.0 and 829.1 µg·h/ml, respectively. In conclusion, a dosing regimen of 200-500 mg/kg 3 times daily is appropriate to obtain serum concentrations in laboratory rats, closely mimicking human serum concentrations over time.

Quantitative Drug Benefit-Risk Assessment

More than 50 % of individuals affected by adverse drug events (ADEs) are older adults. Establishing a drug dosing regimen that balances benefit and risk, and minimizes ADEs in older populations can be challenging. The aim of this study is to evaluate the use of modeling, simulation, and risk-benefit acceptability methods to establish a drug dosing regimen that balances benefit and risk. The study population comprised nondiabetic patients with schizophrenia from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) ≥50 years old, who had been on oral olanzapine for ≥2 weeks. We used mixed-effects modeling based on a preexisting pharmacokinetic model to derive clearance estimates, which were then used to determine the olanzapine area under the concentration-time curve (AUC). Subsequently, with multivariate regression and Monte Carlo simulation, we estimated the olanzapine dose corresponding to the benefit-risk AUC breakpoint. The study population (n = 34) was predominantly male (82.3%) and white (67.6%), with a mean age of 54.4 years and treatment duration of 361.8 days. The mean AUC was 747.6 ng h/mL (95% CI = 524.5, 970.7) for the benefit group (n = 16) and 754.1 (95% CI = 505.9, 1002.4) for the risk group (n = 15). The benefit-risk AUC breakpoint was 524.5 ng h/mL and the corresponding oral olanzapine dose that optimizes benefit-risk balance was 17.8 mg/d. Our study introduces a real-world approach for finding the safe drug dosing regimen without extensive exposure of a vulnerable and older population to drugs. Further studies into the use of modeling, simulation, and risk-benefit acceptability methods to enhance geriatric drug safety are needed.