Steady-state Plasma Concentrations Research Articles

Polymorphisms of Drug-Metabolizing Enzymes and Transporters Contribute to the Individual Variations of Erlotinib Steady State Trough Concentration, Treatment Outcomes, and Adverse Reactions in Epidermal Growth Factor Receptor-Mutated Non-Small Cell Lung Cancer Patients.

BackgroundErlotinib is presently the first line treatment for non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) active mutation. An increasing number of evidences show that the treatment efficacy and toxicities are considerably heterogeneous among individuals. Hence, it is necessary to find biological predictors for further individualized treatment of erlotinib in NSCLC patients.MethodsOur present study enrolled 87 cases of NSCLC patients who had been administrated erlotinib with a fixed dose (150 mg/d). Eleven polymorphisms in seven genes of drug-metabolizing enzymes and transporters were genotyped and the steady state trough concentrations were also determined.ResultsThere were significant variances in the steady-state erlotinib trough plasma concentrations, ranging from 315.6 ng/ml to 4479.83 ng/ml. Erlotinib steady state trough concentration was remarkably lower in current smoking patients. The steady state trough concentration of GG in rs1048943 of CYP1A1 was significantly higher than that of AA allele carriers. The polymorphism of CYP1A2 was significantly associated with the severity of skin rash, and the development of diarrhea was associated with SNPs in ABCB1 and CYP3A5. We also observed that GG allele in CYP1A1 was accompanied with a longer PFS in our study.ConclusionA large variability of erlotinib steady state trough concentration was found among Chinese Han population. SNPs in CYP1A1 appeared to influence the steady state trough concentration of erlotinib. Correlation between CYP1A2 polymorphisms and severity of skin rash was observed, together with the correlation between the development of diarrhea and SNPs in ABCB1 and CYP3A5.

GABAergic modulation of secondary hyperalgesia: A randomized controlled 4-way crossover trial with the α2-subunit preferring GABA positive allosteric modulator, N-desmethyl-clobazam in healthy volunteers.

The antihyperalgesic and sedative effects of the α2-subunit preferring GABAA positive allosteric modulator (GAM), N-desmethyl-clobazam (NDMC), 20 and 60mg, were assessed in a randomized, placebo and active-controlled (clonazepam 1,5mg), 4-way crossover study, in healthy volunteers, using the ultraviolet B-induced experimental pain model. Single (20, 40, 60mg) and repeated doses (20mg over 15days) of NDMC pharmacokinetics were evaluated. Thirty-two subjects participated in the study. Primary outcome parameter was maximal change in the area of cutaneous UVB irradiation-induced secondary hyperalgesia (ASH). ASH decreased under all treatments. Mean (SD) relative change was 79 (22)%, 83 (24)%, 77 (30)% and 92 (16)% for placebo, NDMC20, NDMC60 and clonazepam, respectively. Neither absolute change nor relative change in ASH was significantly different between NDMC60 and placebo (mean difference=2.3cm2 [95% CI 4.0-8.5], p=.462 and 0.4% [-11.9 to 12.6], p=.952, respectively). An overall treatment effect was found on level of sedation. Compared to placebo, sedation was higher under clonazepam (mean difference=39mm [30-49] on a visual analogue scale, p<.001) while NDMC was free of sedative effect. NDMC pharmacokinetics after single doses showed poor absorption, but was linear. Steady-state plasma concentrations of NDMC20 were attained within 14days, with low between-subjects variability. Mean steady-state concentration (CS-S , SD) reached 209 (22) ng/ml. NDMC absence of sedative effect and its overall well-characterized safety coming from years of utilization as a metabolite from clobazam, raise the prospect of dose escalating trials in patients to quantify its clinical utility. SIGNIFICANCE: This article, presenting the Phase I data of the new antihyperalgesic compound, α2-subunit GABAA positive allosteric modulator, N-desmethyl-clobazam (NDMC) is exploring the modulation of a new target in the treatment of neuropathic pain. Based on these results and on its preclinical properties NDMC would qualify as a good tool compound to seek confirmation of the clinical utility of selective GABA allosteric modulators in neuropathic pain patients.

Liver toxicity of anthraquinones: A combined in vitro cytotoxicity and in silico reverse dosimetry evaluation

Anthraquinones are found in a variety of consumer products such as dietary supplements, traditional Chinese medicines, and drugs. Along with their widespread use, potential safety concerns have emerged, especially liver toxicity. Therefore, there is a need to conduct rapid and inexpensive safety assessment for anthraquinones due to a lack of animal and human toxicological data. Here, a combined in vitro cytotoxicity and in silico reverse dosimetry approach was adopted to consider the potential human liver toxicity of 16 anthraquinones and derivatives. First, cytotoxicity (EC50) in two human liver cell lines (HepG2/C3A and HuH-7) was measured under two conditions (single and repeated dosing, 72 h). Second, toxic doses (Dtox) required to yield plasma steady-state concentrations (Css) equal to in vitro EC50 values were predicted by reverse dosimetry simulation using a PBPK model. Finally, Dtox was compared to literature-derived estimated daily intake (EDI) of anthraquinones to assess safety. Among the 16 anthraquinones, rhein was identified as a potential hepatotoxicant due to a combination of cytotoxicity, plasma concentration, and daily intake level. These in vitro and in silico findings provide preliminary data and guidance for further animal and clinical studies to confirm liver toxicity of anthraquinones.

Optimising the dose of clonidine to achieve sedation in intensive care unit patients with population pharmacokinetics.

AimsThe aim of this study was to investigate the population pharmacokinetics (PK) of clonidine in intensive care unit (ICU) patients in order to develop a dosing regimen for sedation.MethodsWe included 24 adult mechanically ventilated, sedated patients from a mixed medical and surgical ICU. Intravenous clonidine was added to standard sedation in doses of 600, 1200 or 1800 μg/d. Within each treatment group, 4 patients received a loading dose of half the daily dose administered in 4 hours. Patients gave an average of 12 samples per individual. In total, 286 samples were available for analysis. Model development was conducted with NONMEM and various covariates were tested. After modelling, doses to achieve a target steady‐state plasma concentration of >1.5 μg/L were explored using stochastic Monte Carlo simulations for 1000 virtual patients.ResultsA 2‐compartment model was the best fit for the concentration‐time data. Clearance (CL) increased linearly with 0.213%/h; using allometric scaling, body weight was a significant covariate on the central volume of distribution (V1). Population PK parameters were: CL 17.1 (L/h), V1 124 (L/70 kg), intercompartmental CL 83.7 (L/h), and peripheral volume of distribution 178 (L), with 33.3% CV interindividual variability on CL and 66.8% CV interindividual variability on V1. Simulations revealed that a maintenance dose of 1200 μg/d provides target sedation concentrations of >1.5 μg/L in 95% of the patients.ConclusionA population PK model for clonidine was developed in an adult ICU. A dosing regimen of 1200 μg/d provided a target sedation concentration of >1.5 μg/L.

Enhanced and Sustained Cutaneous Delivery of Vismodegib by Ablative Fractional Laser and Microemulsion Formulation

Oral administration of vismodegib for basal cell carcinoma treatment is limited by significant class-specific systemic side effects. We investigated the approach of combining ablative fractional laser-assisted drug delivery with an extended-release microemulsion formulation of vismodegib to provide efficient cutaneous delivery invivo. The developed formulation consisted of an oil-in-water microemulsion stabilized by Tween-80. Pig skin was exposed to ablative fractional laser followed by topical application of vismodegib microemulsion for 4 hours. At 4 hours, 2 days, 5 days, and 9 days, we evaluated vismodegib biodistribution in superficial, mid, and deep dermis and plasma (n= 189 measurements) and assessed local skin reactions. Sustained topical delivery of vismodegib was detected in all depths of ablative fractional laser-exposed skin over the course of the study, with peak concentrations found at 5 days and 9 days. The highest vismodegib concentrations reached 1,409.7 μmol/liter in superficial dermis and 62.3 μmol/liter in deep dermis, exceeding steady-state plasma concentrations previously reported for oral administration of vismodegib (5.5-56.0 μmol/liter). Ablative fractional laser increased vismodegib uptake up to 16.6-fold compared with intact skin. Only mild local skin responses to vismodegib were observed, and no vismodegib was detected in plasma. We report sustained topical delivery of vismodegib invivo at high concentrations with favorable skin tolerability, suggesting a future safer vismodegib treatment.

Development of a Physiologically Based Pharmacokinetic Model for Prediction of Pramipexole Pharmacokinetics in Parkinson's Disease Patients With Renal Impairment.

Pramipexole is the first-line medication recommended by the British National Institute for Health and Care Excellence. Pramipexole is predominantly eliminated by renal excretion. The aim was to develop a physiologically based pharmacokinetic (PBPK) model of pramipexole, providing a basis for its individualized administration. The role of glomerular filtration and organic cation transporter 2 (OCT2) in renal tubular secretion was considered. Plasma concentration-time profiles of pramipexole were predicted and validated, first in healthy populations and then in PD patients with varied renal function. Finally, the pharmacokinetics of PD patients with different degrees of renal impairment were predicted. The simulated pharmacokinetic parameters, including maximum plasma concentration (Cmax ), area under the plasma concentration-time curve (AUC), time to maximum plasma concentration (tmax ), and steady-state trough plasma concentration values, obtained using the PBPK model were validated using fold error values, which were all smaller than 2. The successfully validated model supported that OCT2-mediated tubular secretion was affected proportionally to changes in glomerular filtration for various degrees of renal impairment. The predicted AUC0-inf values were increased 1.16-, 1.76-, 3.26-, and 9.48-fold in mild, moderate, and severe renal impairment and end-stage renal disease (ESRD) subjects, resepctively, compared with PD patients with normal renal function. It appears that PD patients with mild renal impairment are unlikely to require dose adjustment (0.125 mg 3 times a day). The pramipexole dose should be reduced to approximately 0.125 mg twice daily, 0.125 mg once daily, and 0.0375 mg once daily in PD patients with moderate renal impairment, severe renal impairment, and ESRD, respectively.

The study of intestinal absorption and biodistribution in vivo of proton pump inhibitors

The major therapeutic strategy for acid-related gastrointestinal diseases in clinic is to reduce the excretion of gastric acid by oral administration of proton-pump inhibitors (PPIs). However, it is quite a challenge to study the oral absorption behaviors of PPIs considering their extreme instability under gastrointestinal environment. As a result, little information has been reported on PPI oral absorption so far, hindering the further development of PPI-contained oral preparations. Here, we first investigated the degradation rate of three representative PPIs, including ilaprazole, ilaprazole sodium and rabeprazole sodium. Then a modified in situ intestine absorption method in rat was established: through the temperature control by the heat exchangers, the perfusate was kept at physiological temperature only when passing through the intestine while it was maintained at 4 °C outside the intestine. Therefore PPIs could maintained sufficiently high stability under proper temperature control. Our data demonstrated that both ilaprazole and ilaprazole sodium exhibited significantly higher absorption efficiency than rabeprazole sodium did through the comparison of their apparent permeability coefficients and steady-state plasma concentrations after perfusion in the duodenum, jejunum, ileum and colon, mainly attributing to their more suitable oil-water partition coefficient. The duodenum could be the best site for the oral absorption of PPIs. Ilaprazole outperformed its sodium salt form with its stable absorption behavior in tested four intestinal segments. Furthermore, after intravenous or oral administration, ilaprazole exhibited a longer residence time and a higher accumulation in the stomach than in most of other tissues/organs. However, it was also found that the accumulation was heterogeneous and mainly located in mucosa cells of the stomach. Our further study indicated that there was no significant difference on the oral absorption efficiency of ilaprazole between female and male rats but ilaprazole underwent a faster metabolism in male rats after oral absorption. Our study provided a valuable guidance for the design of oral formulation and the optimization of PPI-contained formulations.

Impact of genotype-predicted CYP2D6 metabolism on clinical effects and tolerability of metoprolol in patients after myocardial infarction - a prospective observational study.

The β-1 adrenergic receptor blocker metoprolol is primarily metabolized by the polymorphic enzyme cytochrome P 450 2D6 (CYP2D6), an enzyme with substantial genetic heterogeneity. Our purpose was to investigate the impact of CYP2D6 metabolism on clinical effects and tolerability of metoprolol in patients after myocardial infarction (MI). We included 136 patients with MI discharged on treatment with metoprolol with a recommendation to the general practitioner (GP) to increase the metoprolol dose up to 200mg/day within 2months if possible. At follow-up, metoprolol dosage after up-titration, metoprolol steady-state trough plasma concentrations, hemodynamic parameters, potential metoprolol-induced adverse drug reactions and number of visits to the GP were measured. CYP2D6 genotyping including the reduced-function variant alleles CYP2D6*9, CYP2D6*10 and CYP2D6*41 was performed after end of follow-up. According to the genotype-defined CYP2D6 phenotypes, 30% of the patients were metoprolol extensive metabolizers (EMs), 55% intermediate metabolizers (IMs) and 13% poor metabolizers (PMs; carriers of non-coding and reduced-function variant included). Dose-adjusted metoprolol trough concentrations were significantly higher in IM (2-fold) and PM (6.2-fold) groups vs. the EM group (p< 0.001). Only 35% of patients in the PM group achieved the primary end point, i.e. reaching at least 85% of the expected maximum heart rate (HR) during exercise, compared with 78% in the EM group (p< 0.01), and maximum observed HR at exercise was significantly lower in the PM group vs. the EM group (129 ± 5 vs. 142 ± 2bpm, p< 0.007). In contrast, metoprolol maintenance dose, blood pressure, exercise capacity, number of visits at the GP and frequency and severity of self-reported potential metoprolol-related adverse drug reactions were not significantly different between the groups. Using a comprehensive CYP2D6 genotyping panel, the present study demonstrates a > 6-fold increase of dose-adjusted plasma metoprolol trough concentration in CYP2D6 PMs vs. EMs with a parallel lower increase in achieved maximum HR during exercise but without association between genotype and frequency or severity of self-reported adverse drug effects. This may indicate that CYP2D6 PMs potentially could benefit of the increased plasma concentration per dose in a naturalistic setting.

日本人精神疾患患者におけるmirtazapineの水酸化とグルクロン酸抱合：8-OH-mirtazapineのグルクロン酸抱合経路の意義

Introduction To investigate the metabolism of mirtazapine (MIR) in Japanese psychiatric patients, we determined the plasma levels of MIR, N-desmethylmirtazapine (DMIR), 8-hydroxy-mirtazapine (8-OH-MIR), mirtazapine glucuronide (MIR-G), and 8-hydroxy-mirtazapine glucuronide (8-OH-MIR-G). Methods Seventy-nine Japanese psychiatric patients were treated with MIR for 1–8 weeks to achieve a steady-state concentration. Plasma levels of MIR, DMIR, and 8-OH-MIR were determined using high-performance liquid chromatography. Plasma concentrations of MIR-G and 8-OH-MIR-G were determined by total MIR and total 8-OH-MIR (i. e., concentrations after hydrolysis) minus unconjugated MIR and unconjugated 8-OH-MIR, respectively. Polymerase chain reaction was used to determine CYP2D6 genotypes. Results Plasma levels of 8-OH-MIR were lower than those of MIR and DMIR (median 1.42 nmol/L vs. 92.71 nmol/L and 44.96 nmol/L, respectively). The plasma levels (median) of MIR-G and 8-OH-MIR-G were 75.00 nmol/L and 111.60 nmol/L, giving MIR-G/MIR and 8-OH-MIR-G/8-OH-MIR ratios of 0.92 and 59.50, respectively. Multiple regression analysis revealed that smoking was correlated with the plasma MIR concentration (dose- and body weight–corrected, p=0.040) and that age (years) was significantly correlated with the plasma DMIR concentration (dose- and body weight–corrected, p=0.018). The steady-state plasma concentrations of MIR and its metabolites were unaffected by the number of CYP2D6*5 and CYP2D6*10 alleles. Discussion The plasma concentration of 8-OH-MIR was as low as 1.42 nmol/L, whereas 8-OH-MIR-G had an approximate 59.50 times higher concentration than 8-OH-MIR, suggesting a significant role for hydroxylation of MIR and its glucuronidation in the Japanese population.

Relationship Between Plasma Concentrations and Clinical Effects of Cariprazine in Patients With Schizophrenia or Bipolar Mania.

Population pharmacokinetic/pharmacodynamic modeling (via NONMEM) was used to describe longitudinal exposure‐response relationships for total cariprazine (sum of cariprazine and its major active metabolites) in 2,558 patients with schizophrenia or bipolar mania. Drug exposure metrics were explored for potential relationships with efficacy and safety end points. Total cariprazine exposures were significantly related to reductions in Positive and Negative Syndrome Scale (PANSS) or Young Mania Rating Scale (YMRS) total scores in schizophrenia or bipolar mania, respectively, via a maximum effect (E max)‐type relationship. Typical steady‐state plasma concentrations after 3 and 4.5 mg/day were associated with 50% of maximum typical reductions in PANSS and YMRS total scores, respectively. Time‐weighted cariprazine exposures had significant relationships with the probability of common adverse events (AEs). Dose increase was associated with increased efficacy but was also associated with an increase in AEs. Results of these pharmacokinetic/pharmacodynamic analyses support that the recommended dose range (1.5–6 mg/day for schizophrenia and 3–6 mg/day for bipolar mania) provides an appropriate benefit‐risk balance between cariprazine efficacy and safety.

Hormonal status affects plasma exposure of tamoxifen and its main metabolites in tamoxifen-treated breast cancer patients

BackgroundTamoxifen is considered a prodrug of its active metabolite endoxifen, which is dependent on the CYP2D6 and CYP3A enzymes. Tamoxifen pharmacokinetic variability influences endoxifen exposure and, consequently, its clinical outcome. This study investigated the impact of hormonal status on the pharmacokinetics of tamoxifen and its metabolites in TAM-treated breast cancer patients.MethodsTAM-treated breast cancer patients (n = 40) previously believed to have CYP3A activity within the normal range based on oral midazolam and phenotyped as CYP2D6 normal metabolizers using oral metoprolol were divided into two groups according to premenopausal (n = 20; aged 35–50 years) or postmenopausal (n = 20; aged 60–79 years) status. All patients were treated with 20 mg/day tamoxifen for at least three months. Serial plasma samples were collected within the 24 h dose interval for analysis of unchanged tamoxifen, endoxifen, 4-hydroxytamoxifen and N-desmethyltamoxifen quantified by LC-MS/MS. CYP activities were assessed using midazolam apparent clearance (CYP3A) and the metoprolol/alfa-hydroxymetoprolol plasma metabolic ratio (CYP2D6). CYP3A4, CYP3A5 and CYP2D6 SNPs and copy number variation were investigated using TaqMan assays.ResultsPostmenopausal status increased steady-state plasma concentrations (Css) of tamoxifen (116.95 vs 201.23 ng/mL), endoxifen (8.01 vs 18.87 ng/mL), N-desmethyltamoxifen (485.16 vs 843.88 ng/mL) and 4-hydroxytamoxifen (2.67 vs 4.11 ng/mL). The final regression models included hormonal status as the only predictor for Css of tamoxifen [β-coef ± SE, p-value (75.03 ± 17.71, p = 0.0001)] and 4-hydroxytamoxifen (1.7822 ± 0.4385, p = 0.0002), while endoxifen Css included hormonal status (8.578 ± 3.402, p = 0.02) and race (11.945 ± 2.836, p = 0.007). For N-desmethyltamoxifen Css, the final model was correlated with hormonal status (286.259 ± 76.766, p = 0.0007) and weight (− 8.585 ± 3.060, p = 0.008).ConclusionThe premenopausal status was associated with decreased endoxifen plasma concentrations by 135% compared to postmenopausal status. Thus, the endoxifen plasma concentrations should be monitored mainly in the premenopausal period to maintain plasma levels above the efficacy threshold value.Trial registrationRBR-7tqc7k.

Rivaroxaban for Treatment of Pediatric Venous Thromboembolism. an Einstein-Jr Phase 3 Dose-Exposure-Response Evaluation

Background: Venous thromboembolism (VTE) in children occurs with increasing frequency predominantly as a result of hospital-acquired thrombosis leading to a substantial rise in the use of anticoagulant medications in children. Only one anticoagulant (dalteparin, a subcutaneously administered agent) is licensed for use in children, but the evidence to support the use of anticoagulants in children is lacking. While several direct oral anticoagulants have been licensed and are in widespread use in adults, as of yet, none have been licensed for children and child-appropriate formulations are not commercially available. The EINSTEIN-Jr. program is a comprehensive clinical development program aimed at providing data to support the use (and eventual licensure) of rivaroxaban for children with VTE. The recently completed randomized EINSTEIN-Jr. phase 3 study showed similar efficacy and safety for rivaroxaban compared to standard anticoagulation for treatment of pediatric VTE. This abstract reports the results of the dose-exposure-response relationship of rivaroxaban from this study. The pediatric rivaroxaban dosing regimens were established based on phase 1 and 2 data in children and through pharmacokinetic (PK) modeling and has been previously reported. Methods: Rivaroxaban treatment with tablets or the newly-developed granules-for-oral suspension formulation was bodyweight-adjusted and administered once-daily, twice-daily or thrice-daily for children with bodyweights of ≥30, 12-&amp;lt;30, and &amp;lt;12kg, respectively. In children weighing &amp;lt;12kg, the lower range of the adult exposure range was targeted to avoid excessive concentrations at the end of the dosing interval. Previously, these regimens were confirmed for children weighing ≥20kg but only predicted in those &amp;lt;20kg. Based on sparse blood sampling, the 24-hour area under the plasma concentration-time curve [AUC(0-24)ss] and trough [Ctrough,ss] and maximum [Cmax,ss] steady-state plasma concentrations were derived using population PK modeling. Exposure-response graphs were generated to evaluate the potential relationship of individual PK parameters with recurrent VTE, change in thrombus burden at repeat imaging, and bleeding or adverse events. A taste and texture questionnaire was collected from suspension recipients. Results: Between November, 2014 and September, 2018, a total of 365 children were allocated to receive rivaroxaban in the following age groups: birth-&amp;lt;0.5 years (n=13); 0.5-&amp;lt;2 years (n=21); 2-&amp;lt;6 years (n=44); 6-&amp;lt;12 years (n=65); and 12-&amp;lt;18 years (n=173). Of these, 316 (94.3%) were evaluable for PK analyses. A total of 121 (38.3%) children received the rivaroxaban tablet formulation and 195 (61.7%) the suspension formulation. Symptomatic recurrent VTE occurred in 2 children (0.6%) during rivaroxaban treatment. Repeat imaging outcomes in the asymptomatic children were classified as normalized in 124 (39.2%), improved in 125 (39.6%), no relevant change in 16 (5.1%), and deteriorated in 1 (0.3%). In 48 children (15.2%) the result of repeat imaging was uncertain. No major bleeding events occurred with rivaroxaban treatment, whereas clinically relevant non-major bleeding and trivial bleeding were observed in 10 (3.2%) and 111 (35.1%) children, respectively. With respect to the dose-exposure relationship, the vast majority of the individual values were within the 5th-95th percentile for AUC(0-24)ss, Cmax,ss and Ctrough,ss (see figure below on the left). With respect to exposure-response relationship, no clustering was observed for any of the PK parameters with respect to efficacy, bleeding (shown in the figure below on the right), or adverse event outcomes. The results were similar for the tablet and suspension formulation. Acceptability and palatability of the suspension were favorable. Conclusion: Treatment of children with bodyweight-adjusted rivaroxaban regimens resulted in exposures similar to those previously observed in adults receiving 20 mg once daily dosing and the level of exposure was not related to the efficacy, bleeding, or adverse events. Based on this analysis and in conjunction with the previously demonstrated similar efficacy and safety of rivaroxaban compared with standard anticoagulation, we conclude that the bodyweight-adjusted pediatric rivaroxaban regimens with either tablets or suspension are validated and provide a new alternative treatment option for VTE in children. Figure Disclosures Young: Novo Nordisk: Consultancy, Honoraria; Spark: Consultancy, Honoraria; Shire/Takeda: Consultancy, Honoraria; Uniqure: Consultancy, Honoraria; Bioverativ/Sanofi: Consultancy, Honoraria; CSL Behring: Consultancy, Honoraria; Freeline: Consultancy, Honoraria; Genentech/Roche: Consultancy, Honoraria, Research Funding; Grifols: Consultancy, Honoraria; Kedrion: Consultancy, Honoraria. Lensing:Bayer: Employment. Male:Bristol Myers Squibb: Consultancy; Boehringer Ingelheim: Consultancy; Bayer: Consultancy. Kubitza:Bayer: Employment. OffLabel Disclosure: Pediatric treatment of VTE for a drug approved only in adults.

Association of CYP2D6*10 (c. 100 C>T) Genotype with Z-END Concentration in Patients with Breast Cancer Receiving Tamoxifen Therapy in Indonesian Population.

Tamoxifen (TAM) is a frequently used hormonal prodrug for patients with breast cancer that needs to be activated by cytochrome P450 2D6 (CYP2D6) into Zusammen-endoxifen (Z-END). The purpose of the study was to determine the association between CYP2D6*10 (c.100C>T) genotype and attainment of the plasma steady-state Z-END minimal threshold concentration (MTC) in Indonesian women with breast cancer. A cross-sectional study was performed in 125 ambulatory patients with breast cancer consuming TAM at 20 mg/day for at least 4 months. The frequency distribution of CYP2D6*10 (c.100C>T) genotypes (C/C: wild type; C/T: heterozygous mutant; T/T: homozygous mutant) was detected using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), the results of which were subsequently confirmed by sequencing. The genotypes were categorized into plasma Z- END concentrations of <5.9 ng/mL and ≥5.9 ng/mL, which were measured using ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). Percentages of C/C, CT, and T/T genotypes were 22.4%, 29.6%, and 48.8%, respectively. Median (25-75%) Z-END concentrations in C/C, C/T, and T/T genotypes were 9.58 (0.7-6.0), 9.86 (0.7-26.6), and 3.76 (0.9-26.6) ng/mL, respectively. Statistical analysis showed a significant difference in median Z-END concentration between patients with T/T genotype and those with C/C or C/T genotypes (p<0.001). There was a significant association between CYP2D6*10 (c.100C>T) genotypes and attainment of plasma steady-state Z-END MTC (p<0.001). There was a significant association between CYP2D6*10 (c.100C>T) and attainment of plasma steady-state Z-END MTC in Indonesian breast cancer patients receiving TAM at a dose of 20 mg/day.

Rivaroxaban for Treatment of Paediatric Venous Thromboembolism. An EINSTEIN-Jr Phase 3 Dose-Exposure-Response Evaluation

Background: Recently, the randomised EINSTEIN-Jr. study showed similar efficacy and safety for rivaroxaban and standard anticoagulation for acute and continued treatment of paediatric venous thromboembolism (VTE). The rivaroxaban dosing strategy was established based on phase 1 and 2 data in children and through pharmacokinetic (PK) modeling. Methods: Rivaroxaban treatment with tablets or the newly-developed granules-for-oral suspension formulation was bodyweight-adjusted and administered once-daily, twice-daily or thrice-daily for children with bodyweights of ≥30, ≥12-<30, and <12kg, respectively. Previously, these regimens were confirmed for children weighing ≥20kg but only predicted in those <20kg. Based on sparse blood sampling, the daily area under the plasma concentration–time curve [AUC(0-24)ss] and trough [Ctrough,ss] and maximum [Cmax,ss] steady-state plasma concentrations were derived using population PK modeling. Exposure-response graphs were generated to evaluate the potential relationship of individual PK parameters with recurrent VTE, repeat imaging outcomes, and bleeding or adverse events. A taste-and-texture questionnaire was collected for suspension-recipients. Registration NCT02234843; trial completed. Findings: Of the 335 children (aged 0-17 years) allocated to rivaroxaban, 316 (94.3%) were evaluable for PK analyses. Rivaroxaban exposures were within the adult exposure range. No clustering was observed for any of the PK parameters with efficacy, bleeding, or adverse event outcomes. Results were similar for the tablet and suspension formulation. Acceptability and palatability of the suspension were favourable. Interpretation: Based on this analysis and the recently documented similar efficacy and safety of rivaroxaban compared with standard anticoagulation, we conclude that the bodyweight-adjusted paediatric rivaroxaban regimens with either tablets or suspension are validated and provide for appropriate treatment of children with VTE. Trial Registration: EINSTEIN-Jr. (clinicaltrials.gov: NCT02234843) Funding Statement: The study was supported by Bayer AG and Janssen Research & Development, LLC. Declaration of Interests: G.Y. has received honoraria from Bayer AG, Daiichi-Sankyo, and Portola; C.M. has received honoraria from Bayer AG, Boehringer Ingelheim, and Bristol-Myers Squibb; R.K. receiving personal fees from Bayer, Genentech, and Kedrion; P.C. receiving personal fees from Onyx Health Limited; A.K.C.C. receiving personal fees from Bayer and fees, paid to his institution, from Bayer, Pfizer, Daiichi Sankyo, and Bristol-MyersSquibb; G.K. receiving personal fees from Bayer, Boehringer Ingelheim, and DaiichiSankyo and fees, paid to her institution from Pfizer; S.H. receiving personal fees from Pfizer and fees, paid to her institution, from Bayer, Pfizer, and Daiichi Sankyo; A.S. receiving personal fees from Bayer, Pfizer, Daiichi Sankyo and Boehringer Ingelheim; P.A. receiving personal fees and fees, paid to his institution, from Abbvie and Bayer, and fees paid to his institution from Actelion, Novartis, and Daiichi Sankyo; J.B-W. receiving personal fees and fees, paid to his institution, from Bayer, Daiichi Sankyo, DOASENSE and Portola and fees, paid to his institution, from Pfizer; I.M. receiving fees from Sanofi and Bayer; M.P.M. receiving personal fees from Bayer; S.S., V.P., and M.H.P. receiving personal fees from Bayer AG; A.W.A.L., K.T., S.W., W.T.S., S.D.B., and D.K. being employees of Bayer AG; the remaining authors declare no competing financial interests. Ethics Approval Statement: The protocol was approved by the institutional review board of each participating center and written permission from a parent or legal guardian and, when appropriate, child assent, was obtained. The study was conducted in accordance with the Declaration of Helsinki and International Conference on Harmonization Guidelines for Good Clinical Practice.

Exposure-Response Assessment of Enzalutamide and Its Major Metabolites in a Real-World Cohort of Patients with Metastatic Castration-Resistant Prostate Cancer.

Enzalutamide is an oral agent for the treatment of metastatic castration-resistant prostate cancer (mCRPC); N-desmethyl enzalutamide is its active metabolite, which has clinically relevant anti-androgen capacities similar to enzalutamide, and carboxylic acid enzalutamide is an inactive metabolite. The aim of our study was to investigate the relationship between enzalutamide and N-desmethyl enzalutamide exposure and treatment response in a real-world cohort of patients with mCRPC. Retrospective, observational, pharmacokinetic study. Outpatient clinic at a tertiary cancer center in Amsterdam, the Netherlands. Sixty-five patients with mCRPC who were treated with enzalutamide 160mg daily and had at least one steady-state enzalutamide plasma concentration between May 2015 and June 2018; of these patients, 38 were prostate-specific antigen (PSA) responders and 27 were nonresponders. Plasma concentrations, determined by using liquid chromatography with tandem mass spectrometry (LC-MS/MS), were compared between PSA responders and nonresponders. Three clinical end points were evaluated separately in this study: PSA-independent progression-free survival (PFS), time to PSA progression (TTPP), and rate of PSA response (defined as ≥50% decrease in PSA level from baseline). Enzalutamide toxicity was defined as discontinuation due to adverse events, dose reductions due to adverse events, or temporary treatment interruption. For these analyses, plasma concentrations of enzalutamide and N-desmethyl enzalutamide were divided into quartiles. Mean±SD plasma concentrations in the 65 patients were as follows: enzalutamide 11.2±2.8μg/ml, N-desmethyl enzalutamide 9.9±2.9μg/ml, and carboxylic acid enzalutamide 6.1±4.3μg/ml. Plasma concentrations were not significantly different in the PSA responder versus nonresponder groups for enzalutamide (11.5 vs 10.6μg/ml, p=0.20), N-desmethyl enzalutamide (10.1 vs 9.6μg/ml, p=0.48), and carboxylic acid enzalutamide (6.5 vs 5.5μg/ml, p=0.34). Univariate and multivariate analyses did not show a relationship between plasma concentrations and PSA-independent PFS, TTPP, or toxicity. This study confirmed that enzalutamide plasma concentrations were not related to PSA-independent PFS, TTPP, or toxicity in patients with mCRPC, and demonstrated that plasma concentrations of its major metabolites were also not associated with treatment response. Based on these findings, there is no role for therapeutic drug monitoring of enzalutamide in patients with mCRPC in daily practice.

Pharmacokinetic interaction of brivaracetam on other antiepileptic drugs in adults with focal seizures: Pooled analysis of data from randomized clinical trials

ObjectiveTo assess the effect of brivaracetam (BRV) on steady-state plasma concentrations of commonly prescribed antiepileptic drugs (AEDs). MethodsData were pooled from five randomized, double-blind, placebo-controlled efficacy studies (NCT00175929, NCT00175825, NCT00490035, NCT00464269, and NCT01261325) in which adults with refractory epilepsy, and receiving stable doses of 1–2 AEDs, initiated adjunctive treatment with BRV (or placebo) for up to 12 weeks, following a 4–8 week baseline period. Concentrations of carbamazepine, carbamazepine epoxide, clobazam, clonazepam, lacosamide, lamotrigine, levetiracetam, oxcarbazepine (MHD), phenobarbital, phenytoin, pregabalin, topiramate, valproic acid and zonisamide, were measured during baseline and during BRV or placebo evaluation periods. Log-transformed data for patients receiving BRV dosages of 50–200 mg/day (or placebo) were evaluated using repeated measures analysis of covariance. Geometric least-squares means ratios of respective AED concentrations (treatment vs baseline) and their 90% confidence intervals (CIs) were calculated. Relevant interaction of BRV on the respective AED was inferred if CIs were entirely outside of 0.80–1.25 limits. ResultsWithin the population for analysis (n = 1402), relevant interaction was observed for carbamazepine epoxide alone which increased up to 2-fold from baseline due to inhibition of epoxide hydrolase by BRV, and the effect size was not influenced by concomitant valproic acid. Relevant interaction was not observed for other AEDs. ConclusionIn adults with focal seizures, adjunctive BRV treatment does not affect plasma concentrations of the evaluated AEDs but increases carbamazepine epoxide metabolite. Carbamazepine dose reduction should be considered if tolerability issues arise.

P1.14-36 Phase II Trial of Afatinib in Elderly Patients Aged Over 75 Years with EGFR Mutation Positive Non-Small Cell Lung Cancer

Although reports on the use of gefitinib or erlotinib in elderly patients were occasionally found, those on afatinib were rare. According to the analysis of 54 Japanese patients in the LUX-Lung3 study, the dose reduction of afatinib from 40 mg/day was necessary for 76.0% of patients. However, the prolonged administration was possible after a dose reduction to 30 or 20 mg/day, and antitumor effects were maintained with the reduced dose. The efficacy and safety of afatinib at 30 mg/day in PS 0-1 patients who were aged 75 years with EGFR mutation positive chemotherapy-naïve non-small cell lung cancer were studied. The primary endpoint was the response rate (RR), and the planned number of registered cases was set at 35, with a threshold RR of 50%, an expected RR of 75%, α of 0.05, and β of 0.1. The secondary endpoints were progression-free survival (PFS), overall survival (OS), the incidence rate of adverse events (AEs), QOL survey (FACT-L), and trough plasma concentration of afatinib at steady state (PK, collected between the 8th to 15th day after the start of oral administration). The data of 35 patients were collected from May 2015 to August 2017. Patient background was, median age of 79 years (75-92), male/female: 8/27, PS 0/1: 8/27, adenocarcinoma/NSCLC: 30/5, IIIA/IIIB/IV/postoperative recurrence (TNM 7th edition): 2/2/22/9, and exon19del/exon21L858R/exon19del+exon21L858R: 15/19/1. The best overall efficacy was PR/SD/PD/NE: 28/4/1/2, and the RR was 80.0% (95% CI, 63.1-91.6). The median PFS and OS were 16.3 months (95% CI, 11.8-27.0) and not reached, respectively. The main AEs were rash 69%, diarrhea 60%, and paronychia 51%. While the initial afatinib dose was 30 mg, nine (26%) patients continued with 30 mg, 23 (66%) were reduced to 20 mg, and 3 (8%) discontinued due to AEs (2 ILD and 1 stomatitis). Treatment-related death was not observed. There were no significant change of QOL at baseline, after 4, 8, and 12 weeks. PK analyses showed steady state plasma concentration as 22.8 ng/mL which was comparable to reported plasma concentration of 40 mg afatinib in LUX-LUNG3 and 6 (24.3 ng/mL). No obvious PK differences were found according to dose reduction, adverse event, and response. Afatinib at 30 mg/day could be an effective treatment option for elderly patients, over 75 years of age, with good PS. (UMIN 0000177050)

Oral arsenic trioxide ORH-2014 pharmacokinetic and safety profile in patients with advanced hematologic disorders.

Daily intravenous arsenic trioxide administered with all-trans retinoid acid, the standard-of-care for acute promyelocytic leukemia, is costly and challenging to administer. ORH-2014 is a novel, oral arsenic trioxide formulation, consisting of micron-size drug particles with rapid dissolution and high bioavailability. We conducted a multicenter phase 1 dose-escalating study in patients with advanced hematologic malignancies. Twelve patients received ORH-2014 at 5 mg (n=3), 10 mg (n=6), or 15 mg (n=3) orally once a day (fasted state). Objectives were to assess the safety, tolerability and pharmacokinetics of ORH-2014 to support a dose recommendation for future trials. The median age of the patients was 77 years (range: 45-81) and they had received a median of two (range: 1-5) prior therapies. There were no dose limiting toxicities and no drug-related severe adverse events, except one grade III QT prolongation occurring beyond the dose limiting toxicity assessment period and resolving after treatment interruption. ORH-2014 steady-state plasma concentration was reached on day 15. ORH-2014, 15 mg Cmax was comparable to the calculated approved dose of intravenous arsenic trioxide (mean [% coefficient of variation]: 114 [21%] vs. 124 [60%] ng/mL) and area under the curve from 0 to 24 hours was 2,140 (36%) versus 1,302 (30%) h*ng/mL. These results indicate that ORH-2014 at 15 mg is safe, bioavailable, and provides the required arsenic exposure compared to intravenous arsenic trioxide at the approved dose (0.15 mg/kg); this ORH-2014 dose is recommended for future trials. (NCT03048344; www.clin-icaltrials.gov).

Steady-State Plasma Concentrations of Polyethylene Glycol (PEG) are Reached in Children and Adults During Once-Weekly Prophylactic Treatment with Nonacog Beta Pegol (N9-GP)

BackgroundNonacog beta pegol (N9-GP, Refixia®, Rebinyn®) is a human recombinant coagulation factor IX (rFIX) conjugated to a 40-kDa polyethylene glycol (PEG) moiety. PEGylation significantly prolongs the circulation half-life compared with conventional FIX replacement treatments, resulting in higher FIX levels. Although there is extensive clinical experience with PEGylated molecules, the potential for abnormal and/or indefinite PEG accumulation during long-term treatment and the hypothetical impact on long-term safety is still under discussion.AimThe aim of this study was to examine plasma PEG concentrations in children, adolescents and adults undergoing once-weekly intravenous prophylactic treatment with N9-GP for up to 6.5 years.MethodsPlasma samples were collected as part of the PARADIGM clinical development programme (PARADIGM 2/4 [NCT01333111 and NCT01395810] and PARADIGM 5 [NCT01467427]). Proton nuclear magnetic resonance (1H-NMR) was used to measure plasma PEG concentrations.ResultsSteady-state plasma PEG concentrations were reached approximately 6 months after initiation of weekly prophylactic treatment with 40 IU/kg N9-GP. Mean steady-state plasma PEG concentrations were 5.6 μg/mL in children ≤ 12 years old at enrolment (PARADIGM 5) and 5.3 μg/mL in adolescents/adults > 12 years old (PARADIGM 2/4). Plasma PEG concentrations tended to be lower in younger children < 7 years old (mean 4.6 μg/mL). There was a correlation between plasma PEG and FIX activity levels in all age groups.ConclusionPEG steady-state plasma levels were maintained for up to 6.5 years during continuous prophylactic treatment and PEG levels correlated with FIX activity. Apart from the initial increase to steady state, no further systemic PEG accumulation was observed.

Utility of In Vitro Bioactivity as a Lower Bound Estimate of In Vivo Adverse Effect Levels and in Risk-Based Prioritization.

Use of high-throughput, in vitro bioactivity data in setting a point-of-departure (POD) has the potential to accelerate the pace of human health safety evaluation by informing screening-level assessments. The primary objective of this work was to compare PODs based on high-throughput predictions of bioactivity, exposure predictions, and traditional hazard information for 448 chemicals. PODs derived from new approach methodologies (NAMs) were obtained for this comparison using the 50th (PODNAM, 50) and the 95th (PODNAM, 95) percentile credible interval estimates for the steady-state plasma concentration used in in vitro to in vivo extrapolation of administered equivalent doses. Of the 448 substances, 89% had a PODNAM, 95 that was less than the traditional POD (PODtraditional) value. For the 48 substances for which PODtraditional < PODNAM, 95, the PODNAM and PODtraditional were typically within a factor of 10 of each other, and there was an enrichment of chemical structural features associated with organophosphate and carbamate insecticides. When PODtraditional < PODNAM, 95, it did not appear to result from an enrichment of PODtraditional based on a particular study type (eg, developmental, reproductive, and chronic studies). Bioactivity:exposure ratios, useful for identification of substances with potential priority, demonstrated that high-throughput exposure predictions were greater than the PODNAM, 95 for 11 substances. When compared with threshold of toxicological concern (TTC) values, the PODNAM, 95 was greater than the corresponding TTC value 90% of the time. This work demonstrates the feasibility, and continuing challenges, of using in vitro bioactivity as a protective estimate of POD in screening-level assessments via a case study.