Laura Rabinovich-Guilatt

Impact of dosing regimen of custirsen, an antisense oligonucleotide, on safety, tolerability and cardiac repolarization in healthy subjects

AIMS Custirsen (OGX-011/TV-1011), a second-generation antisense oligonucleotide (ASO) that reduces clusterin production, is under investigation with chemotherapy in patients with solid tumours. Custirsen is associated with constitutional symptoms (CS) that may interfere with clinical pharmacology investigations, such as QT interval studies. Experience with other ASOs suggests NSAID premedication may ameliorate CS, but we observed suboptimal outcomes in healthy subjects given custirsen and NSAIDs. We sought to establish a custirsen regimen for future clinical pharmacology studies in healthy subjects. METHODS Subjects received custirsen (640 mg intravenously over 120 min) with dexamethasone premedication or increasing doses (320, 480, 640 mg over 6 days) of custirsen with dexamethasone premedication, then one full custirsen dose without premedication on day 8. Incidence/severity of adverse events (AEs) and extensive electrocardiogram readings were evaluated. Pharmacokinetic parameters were estimated. RESULTS AEs included CS, elevated transaminases and prolonged activated partial thromboplastin time (aPTT) that were predominantly grade 1/2. Administration of increasing custirsen doses and dexamethasone premedication reduced the incidence of CS associated with full dose custirsen. Transaminase elevation showed a dose-dependent effect (0% at days 2, 4, 27% at day 6) with the highest custirsen doses. Increasing doses of custirsen may have mitigated the severity but not incidence of aPTT prolongation. Neither regimen was associated with cardiac repolarization changes in QT values or concentration-effect analyses. The custirsen pharmacokinetic profile was consistent with previous experience. CONCLUSION Escalation of custirsen dose combined with dexamethasone premedication reduced CS associated with full dose custirsen and should be considered in future clinical pharmacology studies of custirsen.

Cardiac safety of rasagiline, a selective monoamine oxidase type B inhibitor for the treatment of Parkinson's disease: a thorough QT/QTc study.

AIMS Rasagiline is a selective, irreversible monoamine oxidase type B inhibitor, developed for the treatment of Parkinsons disease. In compliance with current regulatory requirements, rasagiline underwent a thorough QT/QTc (TQT) study to assess its potential to prolong cardiac repolarization. The primary aim of this study was to evaluate the effects of clinical (1 mg/day) and supratherapeutic (2 mg/day and 6 mg/day) multiple oral doses of rasagiline on the baseline- and placebo-adjusted QTc interval (delta delta QTc (ddQTc)). Other electrocardiogram parameters, pharmacokinetic assessments, safety and tolerability as well as vital signs were investigated. METHODS This was a five-arm, randomized, double-blind, placebo- and active-controlled, and parallel study in healthy subjects. Moxifloxacin (400 mg) positive control was included to demonstrate assay sensitivity. RESULTS 247 of 250 randomized subjects completed the study. Time-matched analysis of ddQTc yielded two-sided 90% confidence intervals for all rasagiline doses below the 10 ms regulatory threshold, showing no effect on cardiac repolarization. Concentration-effect analysis demonstrated no relationships between rasagiline (and its metabolite 1-aminoindan), plasma concentrations, and ddQTc. The pharmacokinetic profile of rasagiline was consistent with previous studies. Adverse events were mild to moderate in intensity and were similar across all treatment groups. There were no clinically significant changes in heart rate and systolic blood pressure. CONCLUSION This TQT study demonstrated a favorable cardiac safety profile of rasagiline.

The effect of mild and moderate renal impairment on the pharmacokinetics of pridopidine, a new drug for Huntington's Disease

Aim Pridopidine, a new oral drug for treatment of patients with motor symptoms associated with Huntingtons Disease (HD) is currently under development. In steady‐state conditions, pridopidine elimination is mediated primarily through renal excretion. This study evaluated single dose and steady‐state pharmacokinetics (PK) of a daily dose of pridopidine in subjects with mild and moderate renal impairment and matched healthy subjects. Methods Subjects with mild renal impairment (n = 12), moderate impairment (n = 12), or their matched healthy controls (n = 25) participated in this study. Subjects received a single dose of pridopidine (45 mg) on day 1 and a multiple dose cycle of 45 mg once daily on days 5–18. Blood and urine samples were collected on days 1 and 18 for PK analysis. Results Mild renal impairment did not affect the PK of pridopidine whilst an increase in exposure was seen in subjects with moderate renal impairment. Subjects with moderate impairment showed reduced plasma clearance (by 44%) and had 68% higher AUC (90% CI 1.22, 2.30) and 26% higher C max (90% CI 1.02, 1.56) values than those with normal renal function at steady‐state. Pridopidine was safe and well tolerated in healthy subjects and in subjects with mild and moderate renal impairment. Conclusions Mild renal impairment has no impact on exposure to pridopidine while moderately impaired renal function resulted in higher pridopidine concentrations.

Evaluation of the Relative Intranasal Abuse Potential of a Hydrocodone Extended-Release Tablet Formulated with Abuse-Deterrence Technology in Nondependent, Recreational Opioid Users

Abstract Objective To assess the intranasal abuse potential of hydrocodone extended-release (ER) tablets developed with CIMA Abuse-Deterrence Technology compared with hydrocodone powder and hydrocodone bitartrate ER capsules (Zohydro ER, original formulation [HYD-OF]). Design Single-dose, randomized, double-blind, quadruple-dummy, active- and placebo-controlled, crossover study. Setting One US site. Subjects Healthy, adult, nondependent, recreational opioid users. Methods Subjects able to tolerate intranasal hydrocodone and discriminate hydrocodone from placebo were eligible for study enrollment. Eligible participants randomly received intranasal hydrocodone ER, intranasal hydrocodone powder, intranasal HYD-OF, intact oral hydrocodone ER, and placebo. Coprimary pharmacodynamic end points were a maximum effect on “at the moment” Drug Liking visual analog scale and Overall Drug Liking visual analog scale. Pharmacokinetics and safety were assessed. Results Mean maximum effect for “at the moment” Drug Liking was significantly (P < 0.01) lower for intranasal hydrocodone ER (72.8) compared with hydrocodone powder (80.2) and HYD-OF (83.2). Similar results were observed for Overall Drug Liking maximum effect (68.5 vs 77.1 and 79.8, respectively; P < 0.01). Secondary end points, including balance of effects and positive, sedative, and other effects, were consistent with these results. Intranasal treatments showed significantly greater effects vs placebo, while intact oral hydrocodone ER was similar to placebo. For each treatment, plasma concentration-time profiles paralleled “at the moment” Drug Liking over time. Incidences of adverse events for intranasal treatments were 52% for hydrocodone ER, 53% for hydrocodone powder, and 61% for HYD-OF. Conclusions The statistically significant differences between hydrocodone ER vs hydrocodone powder and HYD-OF for the primary drug liking end points indicate a lower intranasal abuse potential with hydrocodone ER in healthy, nondependent, recreational opioid users.

Pharmacokinetic and Pharmacodynamic Correlations From 2 Studies Evaluating Abuse Potential of Hydrocodone Extended‐Release Tablets

Pharmacokinetic (PK)/pharmacodynamic (PD) correlations were explored in 2 human abuse potential studies of orally and intranasally administered hydrocodone extended‐release (ER) 45 mg in healthy, nondependent opioid users. In a crossover study design, subjects received intact hydrocodone ER, finely milled hydrocodone ER, and hydrocodone powder in solution in the oral study and finely milled hydrocodone ER, hydrocodone powder, and finely milled Zohydro® ER in the intranasal study. Spearman ρ2 and Pearson r2 values were calculated for PD (maximum effect [Emax] for “at the moment” Drug Liking, Overall Drug Liking, and Take Drug Again visual analog scales [VAS]) vs PK (partial area under the concentration‐time curve [AUC], maximum drug concentration [Cmax], time to Cmax [Tmax], and abuse quotient [PK AQ; Cmax/Tmax]) for all treatments. In the oral study, correlations were strongest between Emax of “at the moment” Drug Liking and PK parameters (Cmax [ρ2 = 0.4446], PK AQ [ρ2 = 0.5179], Tmax [ρ2 = 0.5093], and early systemic exposure [ρ2 = 0.4782]). For Overall Drug Liking and Take Drug Again VAS, ρ2 values for correlations with PK parameters ranged from 0.2620 to 0.3637. In the intranasal study, no clear correlations between PK and PD parameters were apparent.

Pharmacokinetics and safety of single and multiple doses of rasagiline in healthy Japanese and caucasian subjects

As of March 2018, rasagiline is approved for the treatment of Parkinson disease in 55 countries including Japan. The present study evaluated the pharmacokinetics (PK) and safety of rasagiline in healthy Japanese and Caucasian subjects following single and multiple administrations of three rasagiline doses. In this double‐blind, placebo‐controlled study, 64 healthy subjects (32 Japanese and 32 Caucasian) received either rasagiline (0.5, 1.0, or 2.0 mg) or placebo for 10 days with PK sampling for single‐dose administration on day 1 and for multiple administration on day 10. Regardless of administration schedule, rasagiline plasma concentrations and dose‐related increases in exposure parameters were similar between Japanese and Caucasians. Rasagiline accumulation (2‐fold for 0.5 mg and 3‐fold for 1.0 mg and 2.0 mg doses) following multiple administration was similar across the ethnic groups. Geometric mean ratios (GMR) comparing Japanese to Caucasians for AUC0‐24, Cmax and AUCinf following single administration were 1.38, 1.17 and 1.38 for 0.5 mg; 1.22, 1.20 and 1.22 at 1.0 mg; and 1.02, 1.00 and 1.02 at for 2.0 mg. GMR for AUCtau and Cmax,ss following multiple administration were 1.43 and 1.06 at 0.5 mg, 1.06 and 1.00 at 1.0 mg, and 1.09 and 1.07 at 2.0 mg. Safety measures were unremarkable and similar between Caucasian and Japanese subjects. Comparable systemic exposure and safety parameters were demonstrated for rasagiline administered to healthy Japanese and Caucasian subjects.

Pharmacokinetics and Safety of Single‐Dose Inhaled Loxapine in Children and Adolescents

This multisite open‐label study sought to characterize the pharmacokinetics and safety of a single dose of inhaled loxapine in children and adolescents. Loxapine powder for oral inhalation was administered via a single‐use handheld drug device to children and adolescents (aged 10–17 years) with any condition warranting chronic antipsychotic use. Patients were dosed according to body weight and cohort (<50 kg [n = 15], 2.5 or 5 mg; ≥50 kg [n = 15], 5 or 10 mg); the first 6 patients (cohort 1) enrolled in each weight group received the lower dose. Patients were enrolled in the higher‐dose group (cohort 2) after an interim pharmacokinetic and safety analysis of data from cohort 1. Blood samples were collected for 48 hours after dosing to determine the pharmacokinetic profile of loxapine and its metabolites. Safety was assessed using adverse event (AE), laboratory value, physical/neurologic examination, vital sign, electrocardiogram, suicidality, and extrapyramidal symptom assessment. Thirty patients were enrolled and evaluable for pharmacokinetics. Loxapine plasma concentrations peaked by 2 to 5 minutes in most patients; systemic exposure increased with dose in both weight subgroups. Loxapine terminal elimination half‐life was ∼13 to 17 hours. The most common AEs were sedation and dysgeusia. Sedation was severe in 1 patient in the <50‐kg group (2.5‐mg dose) and 1 patient in the ≥50‐kg group (5‐mg dose). No AEs indicative of bronchospasm or other serious AEs were reported. Inhaled loxapine was rapidly absorbed and generally well tolerated in pediatric patients; no new safety signals were observed.

Metoprolol-pridopidine drug–drug interaction and food effect assessments of pridopidine, a new drug for treatment of Huntington's disease

Aims Pridopidine is an oral drug in clinical development for treatment of patients with Huntingtons disease. This study examined the interactions of pridopidine with in vitro cytochrome P450 activity and characterized the effects of pridopidine on CYP2D6 activity in healthy volunteers using metoprolol as a probe substrate. The effect of food on pridopidine exposure was assessed. Methods The ability of pridopidine to inhibit and/or induce in vitro activity of drug metabolizing enzymes was examined in human liver microsomes and fresh hepatocytes. CYP2D6 inhibition potency and reversibility was assessed using dextromethorphan. For the clinical assessment, 22 healthy subjects were given metoprolol 100 mg alone and concomitantly with steady‐state pridopidine 45 mg twice daily. Food effect on a single 90 mg dose of pridopidine was evaluated in a crossover manner. Safety assessments and pharmacokinetic sampling occurred throughout the study. Results Pridopidine was found to be a metabolism dependent inhibitor of CYP2D6, the main enzyme catalysing its own metabolism. Flavin‐containing monooxygenase heat inactivation of liver microsomes did not affect pridopidine metabolism‐dependent inhibition of CYP2D6 and its inhibition of CYP2D6 was not reversible with addition of FeCN3. Exposure to metoprolol was markedly increased when coadministered with pridopidine; the ratio of the geometric means (90% confidence interval) for maximum observed plasma concentration, and area under the plasma concentration–time curve from time 0 to the time of the last quantifiable concentration and extrapolated to infinity were 3.5 (2.9, 4.22), 6.64 (5.27, 8.38) and 6.55 (5.18, 8.28), respectively. Systemic exposure to pridopidine was unaffected by food conditions. Conclusions As pridopidine is a metabolism‐dependent inhibitor of CYP2D6, systemic levels of drugs metabolized by CYP2D6 may increase with chronic coadministration of pridopidine. Pridopidine can be administered without regard to food.

Is it possible to achieve bio-equivalence between an oral solid immediate-release and an analogue enteric-coated formulation?

While bioequivalence between enteric‐coated and immediate‐release formulations can be achieved in terms of AUC, gastric emptying of enteric‐coated dosage forms is a stochastic event, usually leading to lower Cmax values than those observed with the corresponding immediate release. This article examines challenges of developing enteric‐coated dosage forms which are bioequivalent to the corresponding immediate‐release formulations in terms of both AUC and Cmax using rasagiline as a model compound.