Changes In Cmax Research Articles

Evaluation of Age-Related Changes in Teneligliptin Pharmacokinetics in Japanese and European Descent Subjects Using a Physiologically Based Pharmacokinetic Model.

Drugs often show differing pharmacokinetic (PK) profiles, such as higher plasma concentrations, in older people than in younger people owing to age-related decreasesin physiological functions. However, it is difficult to evaluate the PK in older populations. Therefore, we simulated the plasma age-related changes in the PK of teneligliptin, a dipeptidyl peptidase-4 inhibitor, using physiologically based PK (PBPK) models. The previously developed PBPK model was revalidated by comparison between simulated data and clinical study data that included older subjects (up to 75years old). We then simulated the plasma concentration-time profiles for teneligliptin at a dose of 20mg (single and multiple doses) in virtual Japanese (20-70years old) and European descent(20-98years old) subjects. PK parameters were calculated by race and age group. We confirmed the validity of the previous PBPK model by comparison between simulated data and clinical study data. In the evaluation of age-related changes in PK after single and multiple doses using the PBPK model, the area under the plasma concentration-time curve (AUC) of teneligliptin tended to increase slightly with age in both populations up to 70years old. However, no clear age-related change in the maximum plasma concentration (Cmax) of teneligliptin was observed. In the European descent subjects aged ≥ 70years, the AUC tended to increase but the ratio of the change in Cmax was smaller than that in AUC. In both populations, there were positive correlations between AUC and age, but not between Cmax and age. The simulation using a PBPK model showed a tendency for the AUC of teneligliptin to increase with age, whereas Cmax was less affected by age than AUC.

Physiologically-based pharmacokinetic modeling to predict drug-drug interaction of enzalutamide with combined P-gp and CYP3A substrates

Enzalutamide is known to strongly induce cytochrome P450 3A4 (CYP3A4). Furthermore, enzalutamide showed induction and inhibition of P-glycoprotein (P-gp) in in vitro studies. A clinical drug-drug interaction (DDI) study between enzalutamide and digoxin, a typical P-gp substrate, suggested enzalutamide has weak inhibitory effect on P-gp substrates. Direct oral anticoagulants (DOACs), such as apixaban and rivaroxaban, are dual substrates of CYP3A4 and P-gp, and hence it is recommended to avoid co-administration of these DOACs with combined P-gp and strong CYP3A inducers. Enzalutamide’s net effect on P-gp and CYP3A for apixaban and rivaroxaban plasma exposures is of interest to physicians who treat patients for venous thromboembolism with prostate cancer. Accordingly, a physiologically-based pharmacokinetic (PBPK) analysis was performed to predict the magnitude of DDI on apixaban and rivaroxaban exposures in the presence of 160 mg once-daily dosing of enzalutamide. The PBPK models of enzalutamide and M2, a major metabolite of enzalutamide which also has potential to induce CYP3A and P-gp and inhibit P-gp, were developed and verified as perpetrators of CYP3A-and P-gp-mediated interaction. Simulation results predicted a 31% decrease in AUC and no change in Cmax for apixaban and a 45% decrease in AUC and a 25% decrease in Cmax for rivaroxaban when 160 mg multiple doses of enzalutamide were co-administered. In summary, enzalutamide is considered to decrease apixaban and rivaroxaban exposure through the combined effects of CYP3A induction and net P-gp inhibition. Concurrent use of these drugs warrants careful monitoring for efficacy and safety.

Pharmacokinetic Profile of Metformin and SGLT2 Inhibitors alone and in Combination: a Pharmacokinetic Study in Wistar Rats

Objective: To achieve glycemic control, a combination of drugs is eventually necessary, especially the dual therapy of SGLT2 inhibitors with metformin. Despite the value of combination therapy, understanding the pharmacokinetic properties is critical. Therefore, this study aimed to conduct the combined and isolated administration of hypoglycemic drugs to understand their pharmacokinetic properties. Methodology: The study was performed by gavage in twenty-five rats that were divided into five groups: metformin alone (60 mg/kg), canagliflozin alone 20 mg/kg, canagliflozin and metformin (20 mg/kg and 60 mg/kg, respectively), dapagliflozin alone 2 mg/kg, and dapagliflozin and metformin (2 mg/kg and 60 mg/kg, respectively). Blood samples were collected between 0.25 and 36 hours postdose and quantified by an HPLC-MS/MS method. Results: The metformin pharmacokinetics showed values lower than those from literature, but the most relevant result was a significant change in Cmax (3400 ng/mL), AUC (872.4 ng.min/L) and CL/F (72 mL/min/kg) in the metformin with dapagliflozin group compared to metformin alone Cmax (523 ng/mL), AUC (106.8 ng.min/L) and CL/F (752 mL/min/kg). For canagliflozin, the Cmax of 6116.7 ng/mL observed in our study was similar to that observed in literature, while the clearance (5.1 mL/min/kg) was higher than that of literature, which was 3.5 mL/min/kg. Clearance of dapagliflozin CL/F was reported as 3.33 mL/min/kg, while our result was 4.6 mL/min/kg. The same study also published dapagliflozin half-life and MRT, which were slightly lower than our findings. In general, the parameters of canagliflozin and dapagliflozin were similar to the literature and did not change with simultaneous administration with metformin. Conclusion: Dapagliflozin significantly changed the pharmacokinetic disposition of metformin, while metformin coadministration had no influence on the pharmacokinetics of SGLT2 inhibitors

The effect of food on the pharmacokinetics of WXFL10203614, a potential selective JAK1 inhibitor, in healthy Chinese subjects.

Objective: This study was performed to investigate the effect of food on the pharmacokinetics (PK) of WXFL10203614 in healthy Chinese subjects. Methods: This was a randomized, open-label, single-dose, two-treatment (fed vs fasted), two-period, two-sequence, crossover study. 14 eligible subjects were averagely randomized into 2 sequences and then received 10mg WXFL10203614 under fasted or fed condition. In each period, the blood samples were collected from 0h (pre-dose) and serially up to 72h post-dose, and plasma concentrations were detected using the high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method. The effect of food on the PK profile and safety of WXFL10203614 were assessed. Results: 70 subjects were screened, and 14 subjects (10 male and 4 female) were enrolled and completed the study. Under the fasted condition, WXFL10203614 was absorbed rapidly with a Tmax of 0.98h. The absorption rate was slower, Tmax delayed by 2.98h, and the Cmax decreased by 16.3% when WXFL10203614 administered after the high-fat and high-calorie diet, other PK parameters were not affected. The 90% confidence intervals (CIs) for the ratio (fed/fasted) of geometric means of the Cmax, AUC0-t and AUC0-∞ were 0.73-1.01, 0.90-1.03 and 0.90-1.03, indicating that the high-fat and high-calorie diet might impact the absorption process of WXFL10203614. Although the Cmax was slightly decreased, there was no significant difference in the Cmax under fasted and fed conditions. Thus, it was not considered clinically significant owing to the small magnitude of changes in Cmax. All Treatment-emergent adverse events (TEAEs) were mild and resolved spontaneously without treatment. Conclusion: Food had no clinically relevant effects on drug system exposure of WXFL10203614. It was well tolerated under fasted and fed conditions in healthy Chinese subjects, so WXFL10203614 could be administered orally with or without food. Clinical Trial Registration: http://www.chinadrugtrials.org.cn/index.html, identifier CTR20191636.

Dynamic Changes in Gastrointestinal Fluid Characteristics after Food Ingestion Are Important for Quantitatively Predicting the In Vivo Performance of Oral Solid Dosage Forms in Humans in the Fed State.

The aim of this study was to develop a simulation model to predict the in vivo performance of solid oral dosage forms in humans in the fed state. We focused on investigating the effect of dynamic changes in gastrointestinal (GI) fluid characteristics in the fed state on the in vivo performance of solid dosage forms. We used six solid dosage forms containing weak base drugs as model formulations, two with positive food effects in humans, two with negative food effects, and two which are not affected by food ingestion. These model drug formulations were used to perform biorelevant dissolution tests in the stomach and small intestine under both prandial states. The in vitro properties of the drug products obtained from these tests were then coupled with in silico models (fasted or fed) to predict food effects in humans. We successfully incorporated the dynamic changes in GI fluid characteristics and their effects on the in vivo dissolution of drugs into the prediction model for the fed state. This newly designed physiologically based biopharmaceutics modeling approach provided the precise and quantitative prediction of food effects (i.e., changes in Cmax and AUC after food ingestion) in humans while considering the dynamic changes in fluid characteristics in the fed state.

Effect of capmatinib on the pharmacokinetics of substrates of CYP3A (midazolam) and CYP1A2 (caffeine) in patients with MET-dysregulated solid tumours.

Preclinical studies showed that capmatinib reversibly inhibits cytochrome P450 (CYP) 3A4 and CYP1A2 in a time-dependent manner. In this study, we evaluated the effect of capmatinib on the exposure of sensitive substrates of CYP3A (midazolam) and CYP1A2 (caffeine) in patients with mesenchymal-epithelial transition (MET)-dysregulated solid tumours. Besides pharmacokinetics, we assessed treatment response and safety. This open-label, multicentre, single-sequence study consisted of a molecular prescreening period, a screening/baseline period of ≤28 days and a drug-drug interaction (DDI) phase of 12 days. On day 1 of the DDI phase, 37 patients received a single oral dose of midazolam 2.5mg and caffeine 100 mg as a two-drug cocktail. Capmatinib 400 mg bid was administered from day 4 on a continuous dosing schedule. On day 9 of the DDI phase, patients were re-exposed to midazolam and caffeine. After the DDI phase, patients received capmatinib on continuous 21-day cycles until disease progression at the discretion of the investigator. A 22% (90% confidence interval [CI] 7-38%) increase in the midazolam maximum plasma concentration (Cmax ) was noted when administered with capmatinib, but this was deemed not clinically meaningful. Co-administration with capmatinib resulted in 134% (90% CI 108-163%) and 122% (90% CI 95-153%) increases in the caffeine area under the plasma concentration-time curve from time zero to infinity (AUCinf ) and area under the plasma concentration-time curve from time zero to the last measurable point (AUClast ), respectively, with no change in Cmax . Adverse events were consistent with the known capmatinib safety profile. No new safety signals were reported in this study. The data from this study demonstrated that capmatinib is a moderate CYP1A2 inhibitor. Capmatinib administration did not cause any clinically relevant changes in midazolam exposure.

Heart failure as a risk factor of adverse drug reactions. Part 2: potential changes in pharmacokinetics of some drugs

Drug administration, can be potentially associated with adverse drug reactions (ARDs), including serious ones, contributing to an increase in the risk of death or the development of conditions that potentially increase mortality and / or morbidity and / or become the cause of clinical manifestations, requiring the patient to seek medical attention or hospitalization - so called drug-induced diseases (DID). Some pathological conditions, like chronic heart failure (CHF), are potential risk factors for DID due to changes in the pharmacokinetics and pharmacodynamics of drugs. For example, after oral administration of fosinopril, the average T1/2 value in patients with CHF II - III NYHA functional class was 14.2 (±7.3) hours, and in healthy individuals of the control group - 11.0 (±5.2) hours. Values of AUC per os and Cmaxwere also slightly higher in patients with heart failure (HF) than in healthy individuals, and Cl per os, on the contrary, were lower. After intravenous administration of fosinopril, similar results were observed. Another example is the altered absorption of furosemide in patients with decompensated heart failure. Thus, in patients with heart failure, as the edema syndrome is corrected, the time to the onset of the maximum drug concentration in the blood serum (Tmax ) decreases by 27 % and Cmax increases by 29 %, which may indicate a decrease in the slowdown in the absorption rate (by 57 %). Since furosemide is mainly excreted in the urine unchanged, the observed changes in Cmax and Tmax could be associated with delayed gastric emptying, decreased intestinal motility, or edema of the intestinal wall. Individual selection of the dose and dosing regimen, taking into account the characteristics of the pharmacokinetics of drugs in patients with CHF, will help improve the quality of life and prevent potential ADR.

An Assessment of Occasional Bio-Inequivalence for BCS1 and BCS3 Drugs: What are the Underlying Reasons?

Despite having adequate solubility properties, bioequivalence (BE) studies performed on immediate release formulations containing BCS1/3 drugs occasionally fail. By systematically evaluating a set of 17 soluble drugs where unexpected BE failures have been reported and comparing to a set of 29 drugs where no such reports have been documented, a broad assessment of the risk factors leading to BE failure was performed. BE failures for BCS1/3 drugs were predominantly related to changes in Cmax rather than AUC. Cmax changes were typically modest, with minimal clinical significance for most drugs. Overall, drugs with a sharp plasma peak were identified as a key factor in BE failure risk. A new pharmacokinetic term (t½Cmax) is proposed to identify drugs at higher risk due to their peak plasma profile shape. In addition, the analysis revealed that weak acids, and drugs with particularly high gastric solubility are potentially more vulnerable to BE failure, particularly when these features are combined with a sharp Cmax peak. BCS3 drugs, which are often characterised as being more vulnerable to BE failure due to their potential for permeation and transit to be altered, particularly by excipient change, were not in general at greater risk of BE failures. These findings will help to inform how biowaivers may be optimally applied in the future.

Impact of Paroxetine, a Strong CYP2D6 Inhibitor, on SPN-812 (Viloxazine Extended-Release) Pharmacokinetics in Healthy Adults.

SPN‐812 (viloxazine extended‐release) is a novel nonstimulant recently approved as a treatment for attention‐deficit/hyperactivity disorder in children and adolescents. Given that SPN‐812 is metabolized by CYP2D6 and may be coadministered with CYP2D6 inhibitors, this trial investigated the pharmacokinetics and safety of SPN‐812 coadministered with the potent CYP2D6 inhibitor paroxetine. In this single‐sequence, 3‐treatment period study in healthy volunteers, subjects received a single oral dose of 700 mg SPN‐812 alone (period 1), 20 mg daily paroxetine (10 days, period 2), followed by concurrent administration of SPN‐812 and paroxetine (period 3). Blood samples were collected for 72 hours post‐SPN‐812 dosing and analyzed for viloxazine and its primary metabolite, 5‐HVLX‐gluc. Twenty‐two healthy adults were enrolled; all completed the trial. The potential for drug interaction between SPN‐812 and paroxetine was assessed using analysis of variance on the log‐transformed pharmacokinetic parameters Cmax, AUC0‐t, and AUCinf. The least‐squares geometric mean ratios for viloxazine were (reported as the ratio of combination/SPN‐812 alone) Cmax, 116.04%; 90%CI, 109.49%‐122.99%; AUC0‐t, 134.65%; 90%CI, 127.65‐142.03; and AUCinf, 134.80%; 90%CI, 127.94%‐142.03%. CYP2D6 inhibition resulted in a modest change (<35%) on viloxazine AUCs with no change in Cmax. All adverse events were mild in severity.

Opicapone enhances the reversal of MPTP-induced Parkinson-like syndrome by levodopa in cynomolgus monkeys

Opicapone is a third generation nitrocatechol catechol-O-methyltransferase inhibitor that has received regional market approval for use as adjunctive therapy to levodopa in Parkinson's disease patients with motor fluctuations. This study evaluated the effects of opicapone as adjunct to levodopa in reversing a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induced Parkinson's-like syndrome in cynomolgus monkeys in during opicapone preclinical development program. A Parkinson's-like syndrome was induced in cynomolgus monkeys by daily administrations of MPTP. Evaluation of the animals included scoring with the Primate Parkinsonism Motor Rating Scale (PPMRS) and assessment of locomotor activity. MPTP produced a stable Parkinson's-like behavioural syndrome as evidenced by tremor, postural changes, rigidity, impaired movements and balance, (PPMRS scores of 10–15) and decreased locomotor activity (13% of pre-MPTP values). Opicapone treatment alone, for 14 days, did not change Parkinson's-like symptoms nor decreased subject's locomotor behaviour. Ascending combinations of levodopa/benserazide dose-dependently decreased PPMRS and improved locomotor behaviour reaching statistical significance for levodopa/benserazide doses of 18/4.5 mg/kg and those effects were enhanced in opicapone treated subjects. Opicapone treated subjects as compared vehicle-treated, had markedly reduced erythrocyte catechol-O-methyltransferase activity, significantly increased plasma levodopa levels (1.8-fold higher AUC) with no statistically significant changes in Cmax and significantly reduced 3-OMD AUC and Cmax values (7.8- and 6.8-fold respectively). Opicapone potentiated the improvements in Parkinson's-like symptoms produced by levodopa/benserazide combinations with concomitant increase in plasma levodopa exposure, reduction of plasma 3-O-methyldopa levels and erythrocyte catechol-O-methyltransferase activity, results that were later demonstrated in 2 large Phase 3 studies in Parkinson's disease patients.

Pharmacokinetics and safety of revefenacin in subjects with impaired renal or hepatic function.

PurposeRevefenacin, a long-acting muscarinic antagonist for nebulization, has been shown to improve lung function in patients with chronic obstructive pulmonary disease. Here we report pharmacokinetic (PK) and safety results from two multicenter, open-label, single-dose trials evaluating revefenacin in subjects with severe renal impairment (NCT02578082) and moderate hepatic impairment (NCT02581592).Subjects and methodsThe renal impairment trial enrolled subjects with normal renal function and severe renal impairment (estimated glomerular filtration rate <30 mL/min/1.73 m2). The hepatic impairment trial enrolled subjects with normal hepatic function and moderate hepatic impairment (Child-Pugh class B). Subjects received a single 175-µg dose of revefenacin through nebulization. PK plasma samples and urine collections were obtained at multiple time points for 5 days following treatment; all subjects were monitored for adverse events.ResultsIn the renal impairment study, the maximum observed plasma revefenacin concentration (Cmax) was up to 2.3-fold higher and area under the concentration–time curve from time 0 to infinity (AUCinf) was up to 2.4-fold higher in subjects with severe renal impairment compared with those with normal renal function. For THRX-195518, the major metabolite of revefenacin, the corresponding changes in Cmax and AUCinf were 1.8- and 2.7-fold higher, respectively. In the hepatic impairment study, revefenacin Cmax and AUCinf were 1.03- and 1.18-fold higher, respectively, in subjects with moderate hepatic impairment compared with those with normal hepatic function. The corresponding changes in THRX-195518 Cmax and AUCinf were 1.5- and 2.8-fold higher, respectively.ConclusionSystemic exposure to revefenacin increased modestly in subjects with severe renal impairment but was similar between subjects with moderate hepatic impairment and normal hepatic function. The increase in plasma exposure to THRX-195518 in subjects with severe renal or moderate hepatic impairment is unlikely to be of clinical consequence given its low antimuscarinic potency, low systemic levels after inhaled revefenacin administration, and favorable safety profile.

Pharmacokinetics of the Novel Nonsteroidal Mineralocorticoid Receptor Antagonist Finerenone (BAY 94-8862) in Individuals with Mild or Moderate Hepatic Impairment.

Finerenone(BAY 94-8862) is a selective, nonsteroidal mineralocorticoid receptor antagonist. The aim of this study was to assess the effect of mild or moderate hepatic impairment on the pharmacokinetics, safety and tolerability of finerenone. The study was conducted in a single-center, nonrandomized, noncontrolled, nonblinded observational design with group stratification. A single oral 5-mg dose of finerenone was administered as a tablet to participants with mild or moderate hepatic impairment (Child-Pugh A, score 5-6 [n = 9], or Child-Pugh B, score 7-9 [n = 9], respectively) and to age-, weight- and sex-matched healthy participants (n = 9). The pharmacokinetics of finerenone and its metabolites were assessed in plasma and urine, and safety and tolerability were monitored. Finerenone area under the plasma concentration-time curve (AUC) and unbound AUC were 38% and 55% greater, respectively, in participants with moderate hepatic impairment than in healthy participants, whereas maximum plasma concentration (Cmax) was unchanged. No clear effects on AUC or Cmax were seen in participants with mild hepatic impairment. Finerenone was safe and well tolerated in all participants. The effects of mild or moderate hepatic impairment on systemic exposure of finerenone are small, consistent with its low hepatic extraction and preponderance of gastrointestinal over hepatic first-pass clearance. Considering the small increases in AUC and the absence of changes in Cmax, a dose adaptation does not appear to be warranted in patients with mild or moderate hepatic impairment.

Gepirone hydrochloride: a novel antidepressant with 5-HT1A agonistic properties.

Depression is a neuropsychiatric disorder that affects more than 350 million people all over the world. There are psychological and pharmacological treatments for depression which mainly focus on monoaminergic neurotransmission theory. The main concern regarding available antidepressants is the lag period and other side effects, such as sexual dysfunction. Gepirone is a drug of the azapirone group which is a 5-HT1A receptor agonist belonging to the buspirone family. Gepirone is under clinical development and has been shown to be more effective than selective serotonin reuptake inhibitors (SSRIs), as this drug treats the psychiatric disorders without causing sexual dysfunction, which limits the use of SSRIs. It possesses greater selectivity for the 5-HT1A receptor than SSRIs. Clinical studies have shown that gepirone has differential action at pre- and postsynaptic 5-HT1A receptors. Gepirone extended-release tablets (gepirone ER, Travivo) showed promising effects in adult outpatients for the treatment of major depressive disorder (MDD) in a double-blind, randomized, placebo-controlled clinical study. Gepirone also showed an antianxiety effect in a placebo-controlled trial in generalized anxiety disorder. Absorption of gepirone is increased when administered with food as there is no substantial change in Cmax and half-life but it significantly increases AUC and mean residence time. Gepirone undergoes first-pass metabolism and its major metabolites are 1- (2-pyrimidinyl)-piperazine (1-PP) and 3-OH-gepirone, both of which are pharmacologically active. In addition to its better efficacy, gepirone is well tolerated and the major adverse effects observed have been nausea, dizziness and lightheadedness. Evidence from preclinical and clinical studies revealed that gepirone could be a breakthrough therapeutic agent in the treatment of anxiety and MDD.

Differential pharmacokinetic drug-drug interaction potential of eletriptan between oral and subcutaneous routes

1. Pharmacokinetic drug-drug interaction (DDI) data is important from a label claim either in combination drug usage or in polypharmacy situation.2. Eletriptan undergoes first pass related metabolism through CYP3A4 enzyme to form pharmacologically active N-desmethyl metabolite.3. Differential DDI interaction of the concomitant oral dosing of ketoconazole (20.1 mg/kg), a CYP3A4 inhibitor, with oral (4.2 mg/kg) or subcutaneous dose (2.1 mg/kg) of eletriptan was evaluated in male Sprague Dawley rats. Serial pharmacokinetic samples were collected and simultaneously analysed for eletriptan/N-desmethyl eletriptan using validated assay. Non-compartmentally derived pharmacokinetic parameters for various treatments were analysed statistically.4. After oral eletriptan in presence of ketoconazole, Cmax (40 vs. 32 ng/mL alone) and AUCinf (81 vs. 24 ng.h/mL alone) of eletriptan increased; the formation of N-desmethyl eletriptan decreased (Cmax=1.1 ng/mL, 3.9%) with ketoconazole as compared to without treatment (Cmax=3.7 ng/mL, 11.2%). After subcutaneous eletriptan in presence of ketoconazole, there was no change in Cmax (153 vs.152 ng/mL) or AUCinf (267 vs. 266 ng.h/mL) of eletriptan. Formation of N-desmethyl eletriptan after the subcutaneous dose was determined at few intermittent time points with/without ketoconazole.5. Preclinical data support differential DDI of eletriptan when dosed oral vs. subcutaneous, which need to be evaluated in a clinical setting.

Application of physiologically based pharmacokinetic modeling to predict drug disposition in pregnant populations.

Pregnancy is associated with numerous physiological changes that influence absorption, distribution, metabolism and excretion. Moreover, the magnitude of these effects changes as pregnancy matures. For most medications, there is limited information available about changes in drug disposition that can occur in pregnant patients, yet most women are prescribed one or more medications during pregnancy. In this investigation, PBPK modeling was used to assess the impact of pregnancy on the pharmacokinetic profiles of three medications (metformin, tacrolimus, oseltamivir) using the Simcyp® simulator. The Simcyp pregnancy-PBPK model accounts for the known physiological changes that occur during pregnancy. For each medication, plasma concentration-time profiles were simulated using Simcyp® virtual populations of healthy volunteers and pregnant patients. The predicted systemic exposure metrics (Cmax , AUC) were compared with published clinical data, and the fold error (FE, ratio of predicted and observed data) was calculated. The PBPK model was able to capture the observed changes in Cmax and AUC across each trimester of pregnancy compared with post-partum for metformin (FE range 0.86-1.19), tacrolimus (FE range 1.03-1.64) and oseltamivir (FE range 0.54-1.02). Simcyp model outputs were used to correlate these findings with pregnancy-induced alterations in renal blood flow (metformin, oseltamivir), hepatic CYP3A4 activity (tacrolimus) and reduced plasma protein levels and hemodilution (tacrolimus). The results illustrate how PBPK modeling can help to establish appropriate dosing guidelines for pregnant patients and to predict potential changes in systemic exposure during pregnancy for compounds undergoing clinical development.

ELENBECESTAT PHARMACOKINETIC DRUG-DRUG INTERACTIONS INDICATED NO DOSAGE ADJUSTMENTS REQUIRED FOR MOST CONCOMITANT TREATMENTS

Elenbecestat (E2609) is a BACE inhibitor primarily metabolized by carboxylesterase 2 (CES2) and to lesser extent by CYP3A. Drug-drug interaction studies assessed the effects of itraconazole (strong CYP3A and CES2 inhibitor), rifampin (strong CYP3A inducer), and donepezil on elenbecestat pharmacokinetics, as well as the effects of elenbecestat on digoxin (Pgp substrate) pharmacokinetics. This open label study in healthy adult subjects was conducted in 3 parts. Part A: subjects received a single oral dose of elenbecestat 50 mg on day 1; from day 6 to 20, subjects received daily doses of either itraconazole 200 mg or rifampin 600 mg; with a second dose of elenbecestat 50 mg on day 14. Part B: subjects received digoxin 0.25 mg on day 1, elenbecestat 50 mg/day from day 7 to 20, and a second digoxin dose at day 14. Part C: a 3-way crossover study in which each subject received a single dose of elenbecestat 50 mg, elenbecestat 50 mg in combination with donepezil 10 mg, and elenbecestat 50 mg dosed 2 hours before donepezil 10 mg, according to a randomized treatment sequence with ≥21-day washout between treatments. Pharmacokinetic assessments of drugs, including elenbecestat and metabolites M1, M2, and M5, were conducted. Co-administration of elenbecestat and itraconazole resulted in increases in elenbecestat Cmax, AUC(0-inf), and t1/2 compared with administration of elenbecestat alone (Figures). The Cmax of all elenbecestat metabolites decreased with itraconazole co-administration. Co-administration of elenbecestat and rifampin resulted in relatively no change in Cmax or t1/2, a minor decrease in AUC(0-inf), along with pronounced decreases in M2 and M5. In Part B, elenbecestat and digoxin co-administration increased digoxin Cmax slightly, but no changes in overall systemic exposure (AUC) were observed. Co-administration of elenbecestat and donepezil at the same time resulted in non-clinically meaningful increases in Cmax and AUC(0-inf). However, no notable changes in elenbecestat exposure occurred when administered 2 hours before donepezil. Results indicate that itraconazole's interaction was primarily due to CES2 inhibition, therefore, no restrictions or dose adjustments are warranted for elenbecestat when co-administered with CYP3A inhibitors. Furthermore, no dose adjustments are necessary for elenbecestat when co-administered with Pgp substrates or donepezil. The effect of co-administered drugs on elenbecestat pharmacokinetics (expressed as 90% CI of geomean). Donepezil administered * concomitantly or **2 h postdose with elenbecestat Horizontal axis shows fold change in Cmax and AUC relative to control (elenbecestat alone). Note: Generic name elenbecestat is not fixed at this time. The effect of elenbecestat on pharmacokinetics of digoxin (expressed as 90% CI of geomean).

Abstract 2054: Improved delivery of paclitaxel to prostate tumors: a membrane-type matrix metalloproteinase (MT-MMP)-targeted approach

Abstract Introduction : Membrane-type matrix metalloproteinases (MT-MMPs) are highly active in prostate tumours, but absent or inactive in normal tissues. MT-MMPs are also known to be elevated in the majority of solid human tumours and to be central to tumor invasion and angiogenesis. Our objective has been to design inactive prodrugs of paclitaxel that are converted to the active drug by selected MMPs within the prostate tumor microenvironment. Methods and Results : We report the synthesis and biological evaluation of a new series of peptide-based conjugates of paclitaxel designed to be selectively cleaved by MT-MMPs in the tumour microenvironment. Paclitaxel is conjugated to the peptide C-terminus via a self-immolative linker, while the N-terminus is protected from non-specific exopeptidase cleavage through the use of a masking group. The relative importance of individual amino acids within the MT-MMP peptide recognition sequence has been investigated following extensive ex vivo metabolic studies. These studies employed tissue homogenates to assess activation of prodrug conjugates in tumour (PC-3) tissues and stability in normal tissues (liver kidney lung). ICTTax5 emerged as our lead agent, demonstrating in vitro stability in normal tissue with differential release of free paclitaxel in tumour tissue. Further in vivo murine pharmacokinetic studies monitoring paclitaxel release in liver, lung, kidney heart and plasma revealed a substantial increase in tumour exposure to paclitaxel following ICTTax5 prodrug administration (20mg/kg) compared to the molar equivalent dose of paclitaxel alone (7mg/kg). AUC (uM.h) ratios of paclitaxel released from ICTTax5 compared to paclitaxel administered alone were 16.2 for tumour and in the range of 0.05-0.99 for normal tissues. Similar highly significant changes in Cmax were demonstrated with a 10-fold (9.77) increase in tumour concentrations and a substantially decreased Cmax ratio (0.02 - 0.19) in other tissues when administered as ICTTax5. Anti-tumour efficacy studies (PC3 xenografts) resulted in a highly significant growth delay following single dose administration of ICTTax5 [20mg/kg] with paclitaxel alone (7mg/kg; the molar equivalent dose to the paclitaxel released from ICTTax5) having no significant anti-tumour effect. Conclusion : A series of peptide-based prodrug conjugates of paclitaxel were synthesized. ICTTax5 was identified as the lead molecule, enabling selective delivery of active paclitaxel to PC3 prostate tumours resulting in superior pharmacokinetics and efficacy when compared to delivery of paclitaxel alone. Citation Format: Paul M. Loadman, Javier Giménez-Warren, Andrew Mitchell, Amanda D. Race, Jade A. Spencer, Steve D. Shnyder, Jason H. Gill, Robert A. Falconer. Improved delivery of paclitaxel to prostate tumors: a membrane-type matrix metalloproteinase (MT-MMP)-targeted approach. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2054.

Are We Getting the Best Return on Investment From Clinical Drug-Drug Interaction Studies?

Are We Getting the Best Return on Investment From Clinical Drug-Drug Interaction Studies?

Pharmacogenetics of pregnancy‐induced changes in efavirenz pharmacokinetics

Pregnancy-induced physiological changes alter many drugs' pharmacokinetics. We investigated pregnancy-induced changes in efavirenz pharmacokinetics in 25 pregnant and 19 different postpartum women stratified from 211 HIV-positive women in whom a preliminary pharmacogenetic study had been undertaken. Despite significant changes in CL/F during pregnancy (42.6% increase; P = 0.023), median (range) Cmin was 1,000 ng/mL (429-5,190) with no significant change in Cmax (P = 0.072). However, when stratified for CYP2B6 516G>T (rs3745274) genotype, efavirenz AUC0-24 , Cmax and Cmin were 50.6% (P = 0.0013), 17.2% (P = 0.14), and 61.6% (P = 0.0027) lower during pregnancy (n = 8) compared with postpartum (n = 6) in 516G homozygotes, with values of 25,900 ng.h/mL (21,700-32,600), 2,640 ng/mL (1,260-3,490), and 592 ng/mL (429-917), respectively, and CL/F was 100% higher (P = 0.0013). No changes were apparent in CYP2B6 516 heterozygotes (14 pregnant vs. 7 postpartum). The clinical implications of these findings warrant further investigation.

Effects of food and alcohol on the pharmacokinetics of an oral, extended-release formulation of hydrocodone in healthy volunteers.

BackgroundThe purpose of this study was to evaluate the pharmacokinetics, bioavailability, and safety of oral extended-release hydrocodone (HC-ER) when administered with food or alcohol.MethodsTwo single-center, open-label, randomized, crossover studies were conducted in healthy volunteers. In a two-period food-interaction study, 12 subjects received HC-ER 20 mg after an overnight fast and a high-fat meal. In a three-period alcohol-interaction study, 30 naltrexone-blocked subjects received HC-ER 50 mg with a 0%, 20%, or 40% alcohol/orange juice solution after an overnight fast. Pharmacokinetic parameters were derived from plasma concentrations of hydrocodone and its metabolites.ResultsExposure to hydrocodone after HC-ER 20 mg was similar in the fed and fasted states, as assessed by area under the plasma concentration versus time curve from time of dosing to time of last detectable concentration (AUC0–t; 316.14 versus 311.94 ng · h/mL); relative bioavailability (Frel) was 101.74%. Differences (fed versus fasted) in hydrocodone mean maximum plasma concentration (Cmax; 28.86 versus 22.74 ng/mL) and median time to Cmax (tmax; 6 versus 8 hours) were not clinically significant. Administration of 20% alcohol with HC-ER 50 mg did not increase systemic exposure relative to 0% alcohol (AUC0–t 878 versus 832 ng · h/mL; Frel 105%) or result in clinically meaningful changes in Cmax (51.8 versus 46.3 ng/mL) or tmax (5.44 versus 6.16 hours). Administration with 40% alcohol increased AUC0–t (1,008 ng · h/mL versus 832 ng · h/mL; Frel 120%) and Cmax (109 versus 46.3 ng/mL), and shortened tmax (2.43 versus 6.16 hours). Adverse events occurred in 10.0%, 24.1%, and 66.7% of subjects after 0%, 20%, and 40% alcohol, respectively.ConclusionHC-ER can be administered without regard to meals. While there was no evidence of “dose-dumping” (an unintended, rapid release in a short time period of all or most of the hydrocodone from HC-ER), even with 40% alcohol, as with all opioids, alcohol should not be ingested while using HC-ER.