Association of smoking cigarettes, age, and sex with serum concentrations of olanzapine in patients with schizophrenia.

Introduction: Olanzapine is an atypical antipsychotic drug which is effective in the treatment of schizophrenia. Cigarette smoking, age, and sex could be related to the pharmacokinetics and serum concentrations of olanzapine in patients with schizophrenia. The aim of the study was to examine whether there was a significant difference in the serum olanzapine concentrations with regard to the mentioned factors. Materials and methods: A total of 58 outpatients with schizophrenia (37 smokers, 42 men, 35 older than 40 years) participated in the study. Blood was sampled in serum tubes just before taking the next dose of olanzapine. Olanzapine was extracted by liquid-liquid extraction and was measured by an in-house high-performance liquid chromatography method on Shimadzu Prominence HPLC System with diode array detector SPD-M20A (Shimadzu, Kyoto, Japan). The results were expressed as the ratio of concentration to the daily dose of olanzapine (C/D). Non-parametric statistical tests were used to analyse differences between variables. Results: The median C/D of olanzapine (interquartile range) in smokers was 6.0 (3.4-10.2) nmol/L/mg and in non-smokers 10.1 (5.9-17.6) nmol/L/mg; P = 0.007. The median C/D of olanzapine in patients younger than 40 years was 5.6 (4.5-10.2) nmol/L/mg and in patients older than 40 years 8.4 (5.6-13.0) nmol/L/mg; P = 0.105. The median C/D of olanzapine in male patients was 6.6 (4.6-10.4) nmol/L/mg and in female patients 9.0 (5.9-15.3) nmol/L/mg; P = 0.064. Conclusions: The serum olanzapine concentration was significantly lower in smoking than in non-smoking patients with schizophrenia. No significant difference was demonstrated with regard to age and sex.

Designer benzodiazepine rat pharmacokinetics: A comparison of alprazolam, flualprazolam and flubromazolam.

Designer benzodiazepines, including flualprazolam and flubromazolam, are clandestinely produced to circumvent federal regulations. Although flualprazolam and flubromazolam are structurally similar to alprazolam, they do not have an approved medical indication. Flualprazolam differs from alprazolam by the addition of a single fluorine atom. Whereas, flubromazolam differs by the addition of a single fluorine atom and substitution of a bromine for a chlorine atom. The pharmacokinetics of these designer compounds have not been extensively evaluated. In the present study, we evaluated flualprazolam and flubromazolam in a rat model and compared the pharmacokinetics of both compounds to alprazolam. Twelve male, Sprague-Dawley rats were given a 2 mg/kg subcutaneous dose of alprazolam, flualprazolam and flubromazolam and plasma pharmacokinetic parameters were evaluated. Both compounds displayed significant two-fold increases in volume of distribution and clearance. Additionally, flualprazolam displayed a significant increase in half-life leading to a nearly double half-life when compared to alprazolam. The findings of this study demonstrate that fluorination of the alprazolam pharmacophore increases pharmacokinetic parameters including half-life and volume of distribution. The increase in these parameters for flualprazolam and flubromazolam leads to an overall increased exposure in the body and a potential for greater toxicity than alprazolam.

Mechanisms of respiratory depression induced by the combination of buprenorphine and diazepam in rats.

BACKGROUND: The safety profile of buprenorphine has encouraged its widespread use. However, fatalities have been attributed to benzodiazepine/buprenorphine combinations, by poorly understood mechanisms of toxicity. Mechanistic hypotheses include (i) benzodiazepine-mediated increase in brain buprenorphine (pharmacokinetic hypothesis); (ii) benzodiazepine-mediated potentiation of buprenorphine interaction with opioid receptors (receptor hypothesis); and (iii) combined effects of buprenorphine and benzodiazepine on respiratory parameters (pharmacodynamic hypothesis). METHODS: We studied the neuro-respiratory effects of buprenorphine (30 mg kg-1, i.p.), diazepam (20 mg kg-1, s.c.), and diazepam/buprenorphine combination in rats using arterial blood gas analysis, plethysmography, and diaphragm electromyography. Pretreatments with various opioid and gamma-aminobutyric acid receptor antagonists were tested. Diazepam impact on brain 11C-buprenorphine kinetics and binding to opioid receptors was studied using positron emission tomography imaging. RESULTS: In contrast to diazepam and buprenorphine alone, diazepam/buprenorphine induced early-onset sedation (P<0.05) and respiratory depression (P<0.001). Diazepam did not alter 11C-buprenorphine brain kinetics or binding to opioid receptors. Diazepam/buprenorphine-induced effects on inspiratory time were additive, driven by buprenorphine (P<0.0001) and were blocked by naloxonazine (P<0.01). Diazepam/buprenorphine-induced effects on expiratory time were non-additive (P<0.001), different from buprenorphine-induced effects (P<0.05) and were blocked by flumazenil (P<0.01). Diazepam/buprenorphine-induced effects on tidal volume were non-additive (P<0.01), different from diazepam- (P<0.05) and buprenorphine-induced effects (P<0.0001) and were blocked by naloxonazine (P<0.05) and flumazenil (P<0.05). Compared with buprenorphine, diazepam/buprenorphine decreased diaphragm contraction amplitude (P<0.01). CONCLUSIONS: Pharmacodynamic parameters and antagonist pretreatments indicate that diazepam/buprenorphine-induced respiratory depression results from a pharmacodynamic interaction between both drugs on ventilatory parameters.

Safety, pharmacokinetic, pharmacodynamic and clinical activity of molibresib for the treatment of nuclear protein in testis carcinoma and other cancers: Results of a Phase I/II open-label, dose escalation study.

Molibresib is an orally bioavailable, selective, small molecule BET protein inhibitor. Results from a first time in human study in solid tumors resulted in the selection of a 75 mg once daily dose of the besylate formulation of molibresib as the recommended Phase 2 dose (RP2D). Here we present the results of Part 2 of our study, investigating safety, pharmacokinetics, pharmacodynamics and clinical activity of molibresib at the RP2D for nuclear protein in testis carcinoma (NC), small cell lung cancer, castration-resistant prostate cancer (CRPC), triple-negative breast cancer, estrogen receptor-positive breast cancer and gastrointestinal stromal tumor. The primary safety endpoints were incidence of adverse events (AEs) and serious AEs; the primary efficacy endpoint was overall response rate. Secondary endpoints included plasma concentrations and gene set enrichment analysis (GSEA). Molibresib 75 mg once daily demonstrated no unexpected toxicities. The most common treatment-related AEs (any grade) were thrombocytopenia (64%), nausea (43%) and decreased appetite (37%); 83% of patients required dose interruptions and 29% required dose reductions due to AEs. Antitumor activity was observed in NC and CRPC (one confirmed partial response each, with observed reductions in tumor size), although predefined clinically meaningful response rates were not met for any tumor type. Total active moiety median plasma concentrations after single and repeated administration were similar across tumor cohorts. GSEA revealed that gene expression changes with molibresib varied by patient, response status and tumor type. Investigations into combinatorial approaches that use BET inhibition to eliminate resistance to other targeted therapies are warranted.

Exposure-response analysis of adverse events associated with molibresib and its active metabolites in patients with solid tumors.

Molibresib (GSK525762) is an investigational orally bioavailable small-molecule bromodomain and extraterminal (BET) protein inhibitor for the treatment of advanced solid tumors. In the first-time-in-human BET115521 study of molibresib in patients with solid tumors, thrombocytopenia was the most frequent treatment-related adverse event (AE), QT prolongation was an AE of special interest based on preclinical signals, and gastrointestinal (GI) AEs (nausea, vomiting, diarrhea, and dysgeusia) were often observed. The aims of this analysis were the following: (i) develop a population pharmacokinetic (PK)/pharmacodynamic (PD) model capable of predicting platelet time courses in individual patients after administration of molibresib and identify covariates of clinical interest; (ii) evaluate the effects of molibresib (and/or its two active metabolites [GSK3529246]) exposure on cardiac repolarization by applying a systematic modeling approach using high-quality, intensive, PK time-matched 12-lead electrocardiogram measurements; (iii) evaluate the exposure-response (ER) relationship between molibresib and/or GSK3529246 exposures and the occurrence of Grade 2 or higher GI AEs. Overall, the PK/PD model (including a maximal drug effect model and molibresib concentration) adequately described platelet counts following molibresib treatment and was used to simulate the impact of molibresib dosing on thrombocytopenia at different doses and regimens. ER analyses showed no clinically meaningful QT interval prolongation with molibresib at up to 100 mg q.d., and no strong correlation between molibresib exposure and the occurrence of Grade 2 or higher GI AEs. The models described here can aid dosing/schedule and drug combination strategies and may support a thorough QT study waiver request for molibresib.

Influence of Plasma Concentration of Hsa-Mir-370-3p and Cyp2d6*4 On Equilibrium Concentration of Phenazepam in Patients with Recurrent Depressive Disorder.

Introduction: Phenazepam is commonly administered to patients diagnosed with major depressive disorder. Some proportion of such patients do not show adequate response to treatment regimen containing phenazepam, whereas many of them experience type A adverse drug reactions. Previous studies showed that CYP2D6 IS involved in the biotransformation of phenazepam, the activity of which is highly dependent on the polymorphism of the gene encoding it. Objective. The objective of the study was to evaluate the impact of 1846G>A polymorphism of the CYP2D6 gene on the concentration/dose indicator of phenazepam, using findings on enzymatic activity of CYP2D6 (as evaluated by the 6M-THBC/pinoline ratio measurement) and on CYP2D6 expression level obtained by measuring the hsa-miR-370-3p plasma concentration levels in patients suffering from major depressive disorder. Material and methods: The study enrolled 191 patients with recurrent depressive disorder (age -40.0 ± 16.3 years). Treatment regimen included phenazepam in an average daily dose of 6.0 ± 2.3 mg per day. Treatment efficacy was assessed using the validated psychometric scales. Therapy safety was assessed using the UKU Side-Effect Rating Scale. For genotyping and estimation of the microRNA (miRNA) plasma levels we performed the real-time polymerase chain reaction (PCR Real-time). The activity of CYP2D6 was evaluated using the HPLC-MS/MS method by the content of the endogenous substrate of given isoenzyme and its metabolite in urine (6M-THBC/pinoline). Therapeutic drug monitoring has been performed using HPLC-MS/MS. Results: Our findings didn't reveal the statistically significant results in terms of the treatment efficacy evaluation (HAMA scores at the end of the treatment course): (GG) 6.0 [4.0; 8.0] and (GA) 6.0 [5.0; 7.8], p > 0.999; the statistical significance in the safety profile was not obtained (the UKU scores): (GG) 3.0 [2.0; 4.0] and (GA) 3.0 [3.0; 3.0], p > 0.999. We didn't reveal a statistical significance for concentration/dose indicator of phenazepam in patients with different genotypes: (GG) 0.812 [0.558; 1.348] and (GA) 0.931 [0.630; 1.271], p = 0.645). Analysis of the results of the pharmacotranscriptomic part of the study didn't show the statistically significant difference in the hsa-miR-370-3p plasma levels in patients with different genotypes: (GG) 22.5 [16.9; 29.8], (GA) 22.7 [15.7; 31.5], p = 0.695. At the same time, correlation analysis didn't reveal a statistically significant relationship between the phenazepam efficacy profile evaluated by changes in HAMA scale scores and the hsa-miR-370-3p plasma concentration: rs = -0.01, p = 0.866. Also, we didn't reveal the correlation between the miRNA concentration and safety profile: rs = 0.07, p = 0.348. Also we did not reveal the relationship between the CYP2D6 enzymatic activity (as evaluated by 6M-THBC/pinoline ratio measurement) and the hsa-miR-370-3p plasma concentration: rs = -0.14, p = 0.056. At the same time, correlation analysis did not reveal a statistically significant relationship between the phenazepam concentration and the hsa-miR-370-3p plasma concentration: rs = -0.05, p = 0.468. Conclusion: The effect of genetic polymorphism of the CYP2D6 gene on the efficacy and safety profiles of phenazepam was not demonstrated in a group of 191 patients with recurrent depressive disorder. At the same time, hsa-miR-370-3p does not remain a promising biomarker for assessing the level of CYP2D6 expression, because it does not correlate with encoded isoenzyme activity.

Development of a triazolobenzodiazepine-based PET probe for subtype-selective vasopressin 1A receptor imaging.

OBJECTIVES: To enable non-invasive real-time quantification of vasopressin 1A (V1A) receptors in peripheral organs, we sought to develop a suitable PET probe that would allow specific and selective V1A receptor imaging in vitro and in vivo. METHODS: We synthesized a high-affinity and -selectivity ligand, designated compound 17. The target structure was labeled with carbon-11 and tested for its utility as a V1A-targeted PET tracer by cell uptake studies, autoradiography, in vivo PET imaging and ex vivo biodistribution experiments. RESULTS: Compound 17 (PF-184563) and the respective precursor for radiolabeling were synthesized in an overall yield of 49% (over 7 steps) and 40% (over 8 steps), respectively. An inhibitory constant of 0.9 nM towards the V1A receptors was measured, while excellent selectivity over the related V1B, V2 and OT receptor (IC50 >10,000 nM) were obtained. Cell uptake studies revealed considerable V1A binding, which was significantly reduced in the presence of V1A antagonists. Conversely, there was no significant blockade in the presence of V1B and V2 antagonists. In vitro autoradiography and PET imaging studies in rodents indicated specific tracer binding mainly in the liver. Further, the pancreas, spleen and the heart exhibited specific binding of [11C]17 ([11C]PF-184563) by ex vivo biodistribution experiments. CONCLUSION: We have developed the first V1A-targeted PET ligand that is suitable for subtype-selective receptor imaging in peripheral organs including the liver, heart, pancreas and spleen. Our findings suggest that [11C]PF-184563 can be a valuable tool to study the role of V1A receptors in liver diseases, as well as in cardiovascular pathologies.

Pharmacokinetic properties of remimazolam in subjects with hepatic or renal impairment.

BACKGROUND: Remimazolam is a new benzodiazepine for procedural sedation and general anaesthesia. The aim of this study was to characterise its pharmacokinetic properties and safety in renally and hepatically impaired subjects. METHODS: Two separate trials were conducted in patients with hepatic (n=11) or renal impairment (n=11) compared with matched healthy subjects (n=9 and n=12, respectively). The hepatic impairment trial was an open-label adaptive 'Reduced Design' trial, using a single bolus of remimazolam 0.1 mg kg-1 i.v., whereas the renal impairment trial was an open-label trial of a single bolus dose of remimazolam 1.5 mg i.v. Remimazolam plasma concentrations over time were analysed by population pharmacokinetic modelling. RESULTS: Remimazolam pharmacokinetic properties were adequately described by a three-compartment, recirculatory model. Exposure in subjects with severe hepatic impairment was 38.1% higher (i.e. clearance was 38.1% lower) compared with healthy volunteers. This increase caused a slightly delayed recovery (8.0 min for healthy, 12.1 min for moderate, and 16.7 min for severe hepatic impairment). With renal impairment, plasma clearance was comparable with that measured in healthy subjects. Simulations of Cmax after a bolus dose of 10 mg showed no relevant impact of hepatic or renal impairment. The overall incidence of adverse events was low, and all adverse events were mild. CONCLUSIONS: As Cmax after a remimazolam bolus i.v. was not affected by hepatic or renal impairment, no dose adjustments are required. No unexpected adverse events related to remimazolam were seen in subjects with renal or hepatic impairment. CLINICAL TRIAL REGISTRATION: Hepatic impairment trial: ClinicalTrials.gov, NCT01790607 (https://clinicaltrials.gov/ct2/show/NCT01790607). Renal impairment trial: EudraCT Number: 2014-004575-23.

Bioavailability and pharmacokinetic profile of balovaptan, a selective, brain-penetrant vasopressin 1a receptor antagonist, in healthy volunteers.

BACKGROUND: Balovaptan is a potent, selective vasopressin 1a receptor antagonist. The early-phase pharmacokinetics (PK) of balovaptan are reported. RESEARCH DESIGN AND METHODS: Two Phase 1 studies (overall N = 93) assessed single- and multiple-dose balovaptan PK in healthy adults. One (N = 16) assessed absolute oral bioavailability (10 mg or 50 mg) vs a [13C]-balovaptan microdose. The other (N = 77) explored single- (0.5-76 mg) and multiple-dose (14 days; 12-52 mg/day) - randomized 6:2 balovaptan:placebo per dose - PK, dose proportionality, and the effect of food on single-dose (32 mg) Cmax and AUCinf. RESULTS: Absolute balovaptan bioavailability was high (103-116%). Steady-state (Day 14) balovaptan PK was approximately dose proportional with a half-life of 45-47 hours, but single-dose Cmax increased more than dose proportionally and half-life was inversely dose-proportional - a discordance partially attributable to a dose-and-time-dependent volume of distribution. Accumulation (Day 1-Day 14) was inversely dose-proportional (~3.5 [12 mg] to ~1.8 [52 mg]). There was no relevant effect of a high-fat meal on single-dose balovaptan exposure. There were no safety signals: 2/93 subjects discontinued for adverse events. CONCLUSIONS: Balovaptan was well tolerated at single (≤76 mg) and multiple (≤52 mg/day) doses, with a PK profile supportive of once-daily administration without food restrictions. TRIAL REGISTRATION: ClinicalTrials.gov NCT03764449; NCT01418963.

Population pharmacokinetic modeling of molibresib and its active metabolites in patients with solid tumors: A semimechanistic autoinduction model.

Molibresib (GSK525762) is an investigational, orally bioavailable, small-molecule bromodomain and extraterminal (BET) protein inhibitor for the treatment of advanced solid tumors. Molibresib was initially evaluated in a first-time-in-human (FTIH) study BET115521 consisting of two parts: Part 1 of the study (dose escalation) was conducted in 94 patients with nuclear protein in testis midline carcinoma and other solid tumors, and Part 2 (expansion cohort) was conducted in 99 patients with different solid tumor types. Molibresib is metabolized by cytochrome P450 3A4 enzymes to produce two major active metabolites that are equipotent to the parent molecule. The metabolites are measured together after full conversion of one to the other and reported as an active metabolite composite (GSK3529246). The molibresib pharmacokinetic (PK) profile has been characterized by a decrease in exposure over time, with the decrease more pronounced at higher doses, and accompanied by a slight increase of the metabolite concentrations. Autoinduction of molibresib metabolism was suspected and confirmed in vitro. Here we report the development of a semimechanistic liver-compartment population PK model using PK data from the FTIH study, which adequately describes the autoinduction of molibresib clearance and the PK of both molibresib and GSK3529246. Covariate analysis indicated body weight had a significant effect on the volume of distribution of molibresib and GSK3529246, and higher levels of aspartate aminotransferase resulted in the lower clearance of GSK3529246. This model was used to simulate individual patient exposures based on covariate information for use in future alternative dosing strategies and exposure-response analyses.

A population pharmacodynamic Markov mixed-effects model for determining remimazolam-induced sedation when co-administered with fentanyl in procedural sedation.

The clinical effects of remimazolam (an investigational, ultra-short acting benzodiazepine being studied in procedural sedation) were measured using the Modified Observer's Assessment of Awareness/Sedation Scale (MOAA/S). The objective of this analysis was to develop a population pharmacokinetic/pharmacodynamic model to describe remimazolam-induced sedation with fentanyl over time in procedural sedation. MOAA/S from 10 clinical phase I-III trials were pooled for analysis, where data were collected after administration of placebo or remimazolam with or without concomitant fentanyl. A Markov model described transition states for 35,356 MOAA/S-time observations from 1071 subjects. Effect-compartment models of remimazolam and fentanyl linked plasma concentrations to the Markov model, and drug effects were described using a synergistic maximum effect (Emax ) model. Simulations were performed to identify the optimal remimazolam-fentanyl combination doses in procedural sedation. Fentanyl showed synergistic effects with remimazolam in sedation. Increasing age was related to longer recovery from sedation. Patients with body mass index greater than 25 kg/m2 had ~30% higher rates of distribution from plasma to the effect site (keo), indicating a slightly faster onset of sedation. Simulations showed that remimazolam 5 mg was more appropriate than 4 or 6 mg when administered with fentanyl 50 µg. The model and simulations support that a combination of remimazolam 5 mg with fentanyl 50 µg is an appropriate dosing regimen and the dose of remimazolam does not need to be changed in elderly patients, but some elderly patients may have a longer duration of sedation.

Metabolic diversity as a reason for unsuccessful detoxification from benzodiazepines: the rationale for serum BZD concentration monitoring.

PURPOSE: Many harms secondary to benzodiazepine (BZD) dependence force users towards detoxification treatment. However, even strongly motivated patients tolerate the process badly or experience early relapse. The detoxification procedure has not yet been standardized. The objective of this paper is to examine the hypothesis that faulty detoxification routines may have caused some failures. METHODS: The detoxification approaches found in the literature were compared stage by stage. The review was used to identify possible common, across-the-board systematic errors. RESULTS: The presented literature review confirms that the widespread divergence in the BZD metabolism rate is effectively neglected during detoxification routines. Without laboratory measurements, these differences, additionally interfered with by auxiliary drugs, undermine not only the scheduled but even the symptom-driven procedures. An initial substitution with a long-acting BZD, although recommended, may lead to over-accumulation. This excess, varying between patients and incompatible with the current tapering stage, may lead to repeated overestimation of the patient's adjustments to reduced doses. Consequently, the patient's good clinical presentation at withdrawal, resulting in a conclusion of detoxification, may actually reflect a persistently high serum BZD concentration. The low-concentration stage, if shifted past the end of treatment, exposes patients to unexpected, unassisted withdrawal crises. With laboratory feedback, these crises, unlike the symptoms related to deficient re-adaptation mechanisms, could be prevented. Moreover, by minimizing the high-concentration phase, time can be saved for properly assisted low-concentration challenges. CONCLUSION: A customized detoxification procedure driven not only by the intensity of withdrawal symptoms but also by serum BZD monitoring may prevent some failures. As the standard regimen, it would make detoxification from BZDs more reliable and effective.

Population Pharmacokinetics of Remimazolam in Procedural Sedation With Nonhomogeneously Mixed Arterial and Venous Concentrations.

Remimazolam is an ultra-short acting benzodiazepine under development for procedural sedation and general anesthesia. Population pharmacokinetic analysis (PopPK) was conducted for remimazolam with arterial and venous samples previously, but results were limited by arterial-venous concentration differences and inaccurate central volume of distribution (V1) estimates. A new model was developed to describe covariate effects after accounting for arterial-venous differences. Arterial and venous plasma concentration-time data from 11 clinical trials were pooled for PopPK. Data from two constant-rate infusion studies were used to account for venous-to-arterial (VtoA) ratio within residual error and to accurately estimate V1. V1 and VtoA ratio from the pilot model were applied to the full dataset, where the optimal fixed/random effects and covariates were assessed. VtoA ratio was described using a maximum effect (Emax ) model during infusion and as a constant postdose. V1 was estimated as 4.83 L for a 70 kg subject and interindividual variability (IIV) on V1 could only be estimated in studies with early concentrations. IIV on clearance was low (22.9%). Covariates included effects of sex on clearance (women 10% > men), and race on clearance and steady-state volume of distribution (African Americans 16% < other races). Arterial-venous concentration differences were best described using an Emax model during infusion with a constant ratio after infusion, resulting in low residual error (20.7%). There are no clinically relevant dose adjustments needed for any covariates based on pharmacokinetic differences.

Flubromazolam-Derived Designer Benzodiazepines: Toxicokinetics and Analytical Toxicology of Clobromazolam and Bromazolam.

Flubromazolam is widely known as highly potent designer benzodiazepine (DBZD). Recently, the two flubromazolam-derived new psychoactive substances (NPS) clobromazolam and bromazolam appeared on the drugs of abuse market. Since no information concerning their toxicokinetics in humans is available, the aims of the current study were to elucidate their metabolic profile and to identify the isozymes involved in their phase I and phase II metabolism. In vitro incubations with pooled human liver S9 fraction were performed and analyzed by liquid chromatography coupled to orbitrap-based high-resolution tandem mass spectrometry (LC-HRMS-MS). Biosamples after the ingestion of bromazolam allowed the identification of metabolites in human plasma and urine as well as the determination of bromazolam plasma concentrations by LC-HRMS-MS using the standard addition method. In total, eight clobromazolam metabolites were identified in vitro as well as eight bromazolam metabolites in vitro and in vivo. Predominant metabolic steps were hydroxylation, glucuronidation and combinations thereof. Alpha-hydroxy bromazolam glucuronide and bromazolam N-glucuronide are recommended as screening targets in urine. Bromazolam and its alpha-hydroxy metabolite are recommended if conjugate cleavage is part of the sample preparation procedure. The bromazolam plasma concentrations were determined to be 6 and 29 µg/L, respectively. Several cytochrome P450 (CYP) and uridine 5'-diphospho-glucuronosyltransferase (UGT) isozymes were shown to catalyze their metabolic transformations. CYP3A4 was involved in the formation of all phase I metabolites of both NPS, while UGT1A4 and UGT2B10 catalyzed their N-glucuronidation. Several UGT isoforms catalyzed the glucuronidation of the hydroxy metabolites. In conclusion, the determined bromazolam plasma concentrations in the low micrograms per liter range underlined the need for sensitive analytical methods and the importance of suitable urine screening procedures including DBZD metabolites as targets. Such an analytical strategy should be also applicable for clobromazolam.

Effects of Vitamin D Receptor, Cytochrome P450 3A, and Cytochrome P450 Oxidoreductase Genetic Polymorphisms on the Pharmacokinetics of Remimazolam in Healthy Chinese Volunteers.

Remimazolam is a new ultra-short-acting benzodiazepine used to induce and maintain anesthesia and procedural sedation. Its compound structure is similar to midazolam's. Midazolam metabolism might be affected by vitamin D receptor (VDR), cytochrome P450 3A, and cytochrome P450 oxidoreductase genetic polymorphisms. This study investigated the effects of VDR, cytochrome P450 3A, and cytochrome P450 oxidoreductase genetic polymorphisms on the pharmacokinetics of remimazolam in healthy Chinese volunteers after a single intravenous injection of remimazolam besylate. Blood samples were collected from subjects (n = 62) at scheduled time intervals before and after injection. High-performance liquid chromatography-tandem mass spectrometry was used to quantify plasma remimazolam and RF7054 (its inactive carboxylic acid metabolite) concentrations. The relationship between plasma remimazolam concentration, pharmacokinetic parameters, and polymorphic alleles was assessed for each subject. The rs4516035 allele affected the elimination half-life of RF7054 (P = .043), while the rs1544410 allele affected the dose-normalized maximum observed plasma concentration (Cmax /D) of remimazolam (P = .025) in 46 volunteers. Results showed that VDR genetic polymorphisms might affect the pharmacokinetics of remimazolam in the Chinese population.

An Adaptive Physiologically Based Pharmacokinetic-Driven Design to Investigate the Effect of Itraconazole and Rifampicin on the Pharmacokinetics of Molibresib (GSK525762) in Healthy Female Volunteers.

Molibresib (GSK525762), an orally bioavailable small molecule with 2 major equipotent active metabolites, is being developed for the treatment of cancers. Molibresib is a substrate of cytochrome P450 (CYP) 3A4 and P-glycoprotein (P-gp). To enable administering safe doses of molibresib to healthy volunteers, this 2-part randomized, open-label, crossover drug-drug interaction trial was conducted as an adaptive design study using physiologically based pharmacokinetic (PBPK) modeling and simulation to predict the lowest doses of molibresib that could be safely administered alone (10 mg) or with itraconazole and rifampicin (strong inhibitors and inducers of CYP3A and P-gp, respectively). PBPK simulation guided the molibresib dose (5 mg) to be administered along with itraconazole in part 1. Itraconazole increased total exposure (AUC) of molibresib by 4.15-fold with a 66% increase in Cmax , whereas the total AUC and Cmax for the 2 major active metabolites of molibresib decreased by about 70% and 87%, respectively. A second PBPK simulation was conducted with part 1 data to also include the active metabolites to update the recommendation for the molibresib dose (20 mg) with rifampicin. With rifampicin, the AUC and Cmax of molibresib decreased by approximately 91% and 80%, respectively, whereas the AUC of the 2 active metabolites decreased to a lesser extent (8%), with a 2-fold increase in Cmax . The results of this study confirmed the in vitro data that molibresib is a substrate for CYP3A4. The adaptive design, including Simcyp simulations, allowed evaluation of 2 drug interactions of an oncology drug in a single trial, thus minimizing time and exposures administered to healthy subjects.

Pharmacokinetics and pharmacodynamics of intranasal remimazolam-a randomized controlled clinical trial.

PURPOSE: Remimazolam is a novel and ultra-short-acting sedative currently developed for intravenous use in procedural sedation, general anesthesia, and ICU sedation. However, intravenous administration is not always appropriate, depending on the patient or setting. This study evaluated intranasal administration as a potential alternative route. METHODS: The study used a randomized, double-blind, 9 period cross-over design to compare the pharmacokinetics, pharmacodynamics, and safety of single intranasal doses of 10, 20, and 40 mg remimazolam (as powder or solution) with intranasal placebo and 4 mg intravenous remimazolam. RESULTS: Intranasal remimazolam powder had a consistent absolute bioavailability of approximately 50%; Tmax was 10 min; AUC and Cmax were dose-proportional. The higher doses of intranasal solution, however, resulted in decreasing bioavailability and loss of dose-proportionality in AUC and Cmax despite complete drug absorption due to partial swallowing of dose and the resulting first-pass effect. Pharmacodynamics were generally consistent with PK. Peak effects (drowsiness, relaxation, any, memory, response time) were in similar ranges after intranasal (10 to 40 mg) as intravenous (4 mg) dosing and were partially, but not consistently, dose-related. Safety results were generally consistent with other benzodiazepines; however, intranasal remimazolam (but not placebo) caused nasal discomfort/pain, in some cases even severe. CONCLUSIONS: Intranasal administration of remimazolam was safe and caused sedative effects. However, the severe pain and discomfort caused by intranasal remimazolam prohibit its use by this route of administration, at least with the currently available intravenous formulation.

Remimazolam Has Low Oral Bioavailability and No Potential for Misuse in Drug-Facilitated Sexual Assaults, with or Without Alcohol: Results from Two Randomised Clinical Trials.

BACKGROUND AND OBJECTIVES: Remimazolam is a new ultra-short-acting benzodiazepine currently being developed for intravenous use in procedural sedation, general anaesthesia, and intensive care unit sedation. Benzodiazepines represent a drug class associated with drug-facilitated sexual assaults, especially in combination with alcohol. Two clinical trials were designed to evaluate the oral bioavailability and pharmacokinetics/pharmacodynamics of remimazolam and to assess the potential for remimazolam misuse in drug-facilitated sexual assaults via oral ingestion. METHODS: Trial 1 was conducted in 14 healthy volunteers to evaluate the oral bioavailability of remimazolam. Part 1 of trial 2 was conducted in 21 healthy female volunteers to find the minimal biologically active dose of oral remimazolam. Part 2 of trial 2 was conducted in 11 healthy female volunteers to evaluate the pharmacokinetics/pharmacodynamics of oral remimazolam in combination with alcohol. RESULTS: Remimazolam undergoes rapid and extensive first-pass metabolism upon oral administration. The oral bioavailability of remimazolam was negligible (2.2% based on total systemic exposure and 1.2% based on maximum plasma concentration). Plasma clearance of both remimazolam and its metabolite was fast (elimination half-life 20‒40 min and 1.75‒2 h, respectively). Alcohol did not appear to inhibit the rapid first-pass metabolism of remimazolam. No clear sedative effects were observed for remimazolam without alcohol. Significant sedation was observed in one of ten subjects after remimazolam 360 mg (18 drug product vials) + 40% v/v alcohol. CONCLUSION: The oral bioavailability of remimazolam is negligible, which-together with its distinct bitter taste-suggests no meaningful potential for misuse in drug-facilitated sexual assaults via oral ingestion, with or without alcohol. CLINICAL TRIAL REGISTRATION NUMBERS: Trial 1 (NCT04113564) and trial 2 (NCT04113343) both retrospectively registered on 2 October 2019.

Tamrintamab pamozirine (SC-003) in patients with platinum-resistant/refractory ovarian cancer: Findings of a phase 1 study.

OBJECTIVE: Epithelial ovarian carcinoma (EOC) is diagnosed at advanced stage in the majority of women and, despite being initially chemosensitive, eventually recurs and develops resistance to known therapies. SC-003 is a pyrrolobenzodiazepine-based antibody-drug conjugate targeting dipeptidase 3 (DPEP3), a membrane-bound dipeptidase associated with tumor-initiating cells in patient-derived EOC xenograft models. This first-in-human phase 1a/1b study evaluated the safety/tolerability, pharmacokinetics, and preliminary antitumor activity of SC-003 alone or in combination with budigalimab (formerly ABBV-181), an antibody targeting PD-1, in patients with platinum-resistant/refractory EOC (NCT02539719). METHODS: Patients received SC-003 at 1 of 6 dose levels (0.025-0.4 mg/kg) every 3 weeks (Q3W), utilizing a standard 3 + 3 design (dose-limiting toxicity [DLT] period: 21 days). Patients with DPEP3-positive tumors were enrolled in the dose-expansion phase of the study and treated with SC-003 monotherapy or in combination with budigalimab. RESULTS: Seventy-four patients (n = 29, dose escalation; n = 45, dose expansion; n = 3 budigalimab combination) were enrolled and received ≥1 dose of study drug. One DLT occurred (grade 3 ileus) but was considered unrelated to study drug. The MTD for the Q3W schedule was 0.3 mg/kg and the SC-003 doses selected for the dose-expansion phase of the study were 0.3 mg/kg and 0.2 mg/kg. The most common treatment-emergent adverse events were fatigue, nausea, decreased appetite, pleural effusion, abdominal pain, and peripheral edema. The overall response rate was low (4%), and responses were not durable. Post-hoc examination of antitumor activity suggested a higher response rate in patients with higher DPEP3 expression. CONCLUSIONS: SC-003 lacked the requisite safety profile and antitumor activity to warrant further development.

Pharmacokinetic Variability During Long-Term Therapeutic Drug Monitoring of Valproate, Clobazam, and Levetiracetam in Patients With Dravet Syndrome.

BACKGROUND: The use of therapeutic drug monitoring (TDM) for antiseizure medications (ASMs) may contribute to treatment optimization in individual patients. This study included patients with Dravet syndrome as they often require close monitoring because of polypharmacy with various ASMs. The aim was to use long-term TDM to investigate pharmacokinetic variability of ASMs in these patients. METHODS: Retrospective data from patients with Dravet syndrome were collected from the TDM database at the Section for Clinical Pharmacology, National Center for Epilepsy in Norway (2008-2018). Concentration/(dose/kg)ratios (C/D ratios) were calculated for the ASMs and the concentration (C/C ratio) for N-desmethylclobazam. In patients with at least 3 measurements, the CV for C/D ratios for intrapatient and interpatient variability was calculated. RESULTS: Fifty-three patients (30 male patients/23 female patients) between 2 and 50 years of age (mean, 16 years) were included. Pharmacokinetic variability of the total number of measurements of valproate (n = 417), clobazam and N-desmethylclobazam (n = 328), and levetiracetam (n = 238) was determined. Interpatient variability was more pronounced than intrapatient variability (coefficient of variations: valproate, 65% vs. 24%; levetiracetam, 71% vs. 27%; and clobazam/N-desmethylclobazam, 47%/77% vs. 35%/55%) (P < 0.01). Comedication with stiripentol (n = 16) increased the C/D ratio of valproate by 63% and of clobazam by 133% and the C/C ratio of N-desmethylclobazam/clobazam by 104% (P < 0.05). Younger age also contributed to pharmacokinetic variability. CONCLUSIONS: Long-term TDM revealed extensive variability in serum concentrations over time; the variability was lowest for levetiracetam, moderate for valproate, and highest for clobazam. Pharmacokinetic variability and interactions can thus be identified and adjusted to facilitate decision making to achieve the optimal treatment outcome.