Clinical Pharmacology in Drug Development最新文献

Etrasimod is an investigational, once-daily, oral, selective sphingosine 1-phosphate receptor 1,4,5 modulator in development for immune-mediated inflammatory diseases (IMIDs). Here, we report the human safety, pharmacokinetics, and pharmacodynamics of etrasimod obtained from both a single ascending dose (SAD; 0.1-5 mg) study and a multiple ascending dose (MAD; 0.35-3 mg once daily) study. Overall, 99 healthy volunteers (SAD n = 40, MAD n = 59) completed the 2 studies. Evaluated single and multiple doses were well tolerated up to 3 mg without severe adverse events (AEs). Gastrointestinal disorders were the most common etrasimod-related AEs. Over the evaluated single- and multiple-dose ranges, dose-proportional and marginally greater-than-dose-proportional etrasimod plasma exposure were observed, respectively. At steady state, etrasimod oral clearance and half-life mean values ranged from 1.0 to 1.2 L/h and 29.7 to 36.4 hours, respectively. Dose-dependent total peripheral lymphocyte reductions occurred following etrasimod single and multiple dosing. Etrasimod multiple dosing resulted in reductions from baseline in total lymphocyte counts ranging from 41.1% to 68.8% after 21 days. Lymphocyte counts returned to normal range within 7 days following treatment discontinuation. Heart rate lowering from pretreatment baseline on etrasimod dosing was typically mild, with mean reductions seen after the first dose of up to 19.5 bpm (5 mg dose). The favorable safety, pharmacokinetic, and pharmacodynamic properties of etrasimod in humans supported its further development and warranted its investigation for treatment of IMIDs.

Osteoarthritis (OA) pain management options are currently limited. Fasinumab, an anti-nerve growth factor monoclonal antibody, has been investigated in healthy volunteers and patients with OA-related pain, among other conditions. Data from 12 Phase I-III clinical trials of 92 healthy volunteers and 7430 patients with OA were used to develop a population pharmacokinetic model to characterize fasinumab concentration-time profiles and assess the covariates’ effect on fasinumab pharmacokinetic parameters. Participants received single or repeated fasinumab doses intravenously (IV)/subcutaneously (SC), based on body weight (0.03-1 mg/kg IV or 0.1-0.3 mg/kg SC)/fixed dose (9-12 mg IV or 1-12 mg SC). Fasinumab concentration-time data following IV and SC administration in healthy volunteers and patients with OA-related pain were adequately described by a 2-compartment model. Bioavailability increased with higher doses; estimated at 55.1% with 1 mg SC dose, increasing in a greater-than-proportional manner above this. Body weight had the largest predicted impact on fasinumab steady-state exposures, participants at the 5th and 95th percentiles had a 43%-45% higher/22%-23% lower exposure versus reference, respectively. Other covariates had small but clinically irrelevant impacts.

Voriconazole is a second-generation, synthetic, triazole antifungal drug based on the structure of fluconazole. We compared the safety, tolerability, and pharmacokinetic characteristics of voriconazole for injection (200 mg) manufactured by at a dose of 6 mg/kg in Chinese healthy adult volunteers. This was a single-center, randomized, open, 2-preparation, single-dose, 2-period, 2-sequence, crossover bioequivalence clinical trial. Twenty-four eligible, healthy, male, and female volunteers were assigned randomly to one of 2 dose-sequence groups (test-reference group or reference-test group) in a 1:1 block. The voriconazole concentration in plasma was determined by protein precipitation and high-performance liquid chromatography-tandem mass spectrometry. The main PK parameters were calculated on the basis of a noncompartmental model. The ratio of the geometric mean of the maximum plasma drug concentration, area under the plasma concentration–time curve from time 0 to the last time of quantifiable concentration, and area under the plasma concentration-time curve from time 0 to infinity of the test preparation, and the reference preparation was 100.4%, 102%, and 102.2%, respectively. The 90% confidence intervals were between 80% and 125%, indicating that the 2 preparations were bioequivalent. The adverse events experienced by healthy adult volunteers were mild. Both preparations had a good safety profile.

Etripamil, a fast-acting nondihydropyridine L-type calcium channel blocker, is under investigation for potential self-administration for the acute treatment of supraventricular tachyarrhythmias in a medically unsupervised setting. We report detailed pharmacokinetics and pharmacodynamics of intranasally administered etripamil in healthy adults from 2 Phase 1, randomized, double-blind studies: Study MSP-2017-1096 (sequential dose-escalation, crossover study design, n = 64) and NODE-102 (single dose, 4-way crossover study, n = 24). Validated bioanalytical assays determined plasma concentrations of etripamil and its inactive metabolite. Noncompartmental pharmacokinetic parameters were calculated. Pharmacodynamic parameters were determined for PR interval, blood pressure, and heart rate. Etripamil was rapidly absorbed intranasally, with time to maximal plasma concentration of 5-8.5 minutes, corresponding to a rapid greater than 10% increase in mean maximum PR interval from baseline within 4-7 minutes of doses of 60 mg or greater. Following peak plasma concentrations, systemic etripamil levels declined rapidly within the first 15 minutes following dosing and decreased more gradually thereafter. PR interval prolongation greater than 10% from baseline was generally sustained for about 45 minutes at doses of 60 mg or greater. The mean terminal half-life ranged from about 1.5 hours with 60 mg to about 2.5-3 hours for the 70- and 105-mg doses. Etripamil was generally well tolerated without symptomatic hypotension. Adverse events were primarily mild to moderate and related to the administration site; no serious adverse events or episodes of atrioventricular block occurred. Intranasal etripamil administration, at doses of 60 mg or greater, produced rapidly occurring slowing of atrioventricular nodal conduction with a limited duration of effect without hemodynamic or electrocardiographic safety signals in healthy volunteers.

Baxdrostat is a selective small-molecule aldosterone synthase inhibitor in development for treatment of hypertension and chronic kidney disease. This phase 1, open-label, parallel-group study assessed the safety and pharmacokinetics (PK) of baxdrostat in participants with varying degrees of renal function. Participants were enrolled into control (estimated glomerular filtration rate [eGFR] ≥60 mL/min), moderate to severe renal impairment (eGFR 15-59 mL/min), or kidney failure (eGFR <15 mL/min) groups and received a single 10-mg baxdrostat dose followed by 7 days of inpatient PK blood and urine sampling. Safety was assessed by adverse events, clinical laboratory evaluations, vital signs, physical examinations, and electrocardiograms (ECGs). Thirty-2 participants completed the study. There were no deaths and only 1 mild drug-related adverse event (diarrhea). No clinically meaningful changes in laboratory values, vital signs, physical examinations, or ECGs occurred. Plasma concentration-time curves of baxdrostat were similar among all groups. Urine PK parameters were similar (approximately 12% excreted) in the moderate to severe renal impairment and control groups. Inadequate urine production in the kidney failure group resulted in minimal urinary baxdrostat excretion. Renal impairment had no significant impact on systemic exposure or clearance of baxdrostat, suggesting that dose adjustment due to PK differences in patients with kidney disease is unnecessary.

With an emphasis on the disappointing limited impact of naloxone in reducing opioid overdose deaths, Sellers and Romach¹ raise a number of compelling arguments. Their view is supported by data from the Centers for Disease Control and Prevention: According to the State Unintentional Drug Overdose Reporting System database, naloxone had been administered in more than 20% of opioid-related overdose deaths nationally, with some jurisdictions reporting that more than 35% of decedents had received naloxone.² Thus, the estimated death toll from opioid overdoses exceeded 85,000 for the 12-month period ending July 2023³ despite the availability of multiple naloxone products and naloxone saturation strategies.⁴ More than 90% of these fatalities were attributed to high-potency synthetic opioids (synthetics) such as fentanyl.³

In addition to the points raised by Sellers and Romach,¹ these data raise another fundamental issue: Is the availability of standard naloxone tools (ie, doses of 4 mg intranasal and 2 mg/2 mL intramuscular) available in a community setting sufficient to effectively reverse a synthetic opioid overdose?

There is now compelling evidence^5-8 that rapid delivery of higher doses of naloxone are needed to reverse an overdose involving synthetics compared to morphinan-based molecules such as morphine and heroin. Synthetics have a more rapid onset of action than morphinans,^{5, 6} which reduces the window of opportunity to successfully reverse an overdose. Both the shorter time to maximum concentration (t_max; 0.25 hours) and higher maximum concentration (C_max; 12.2 ng/mL)⁹ of intranasal nalmefene (2.7 mg), when taken together with a higher affinity at μ-opioid receptors,⁶ are consistent with a more rapid onset of action compared to intranasal naloxone (t_max 0.5 hours and C_max 5.3 ng/mL, respectively).⁶ However, in an overdose involving synthetics, antagonist exposure during the crucial first few minutes after dosing is far more significant⁷: In this regard, plasma nalmefene concentrations 5 minutes after administration⁹ are approximately 3-fold higher than following intranasal naloxone.⁶ A more rapid onset of action is also supported by comparative efficacy data in a clinical model of opioid-induced respiratory depression.¹⁰ In this study, intranasal nalmefene led to a reversal of remifentanil-induced reductions in minute ventilation that was almost twice as high as the reversal produced by intranasal naloxone (5.75 vs 3.01 L/min; P less than .0009) at 5 minutes after administration, the primary end point).

The dose of nalox

This Journal recently published a paper describing the pharmacokinetics of a recently Food and Drug Administration (FDA) approved device for intranasal administration of the opioid receptor antagonist nalmefene.¹ Parenteral nalmefene was approved in 1995, but was subsequently withdrawn from the market by the manufacturer because of lack of market success. The new formulation (Trade Name Opvee, Indivior Inc., Richmond, VA) is “indicated for the emergency treatment of known or suspected overdose induced by natural or synthetic opioids in adults and pediatric patients aged 12 years and older, as manifested by respiratory and/or central nervous system depression”. The basis of this approval was nalmefene's high affinity as an antagonist at the mu opioid receptor, the apparent safety of nalmefene in humans, the pharmacokinetic similarity to intramuscular nalmefene, and the demonstration of changes in minute ventilation in an experimental ventilatory model assessed in non-dependent healthy subjects who received an infusion of remifentanil.

Despite the reportedly favorable pharmacokinetic profile of intranasal nalmefene, the likelihood that this new formulation will play a critical role in preventing opioid overdose deaths in the context of the public health opioid epidemic is questionable given the challenges that have confronted the widely known opioid receptor antagonist naloxone.²

Naloxone, a pure opioid receptor antagonist, has been approved since 1971, is widely available, and can safely reverse the opioid induced respiratory depression and prevent deaths in medical and non-medical settings.³ While naloxone is available in intranasal, intravenous, and intramuscular formulations and is effective in preventing opioid overdose death of individuals, the number of opioid overdose deaths continues to rise (about 80,000 per year).⁴ This limited impact is disappointing but not surprising given the many practical obstacles associated with the use of opioid receptor antagonists, including the following: distribution of naloxone to the location of opioid overdose; providing training to first responders; direct and indirect cost of naloxone (in some cases naloxone is more expensive than the street price of opioids and other drugs); bias and prejudice about individuals who have opioid used disorder (OUD); a mismatch of the at-risk population to the available health services for immediate and longer term management of OUD; and a resistance by many opioid users to receive an antagonist and/or enter treatment. These challenges are further exacerbated by pervasive socio-economic factors, wide geographic variation in overdose rates, and uneven access to and cost of healthcare.

Intranasal nalmefene, like naloxone administered by similar routes, is rapidly absorbed. Theoretically the longer half-life of nalmefene (mean 11.3 hours compared to 30-90 minu

Icenticaftor (QBW251) is a potentiator of the cystic fibrosis transmembrane receptor. Based on its mechanism of action, icenticaftor is expected to provide benefits in patients with chronic obstructive pulmonary disease by restoring mucociliary clearance, which would eventually lead to a reduction of bacterial colonization and related inflammatory cascade. A placebo- and positive-controlled, 4-way crossover thorough QT study was conducted in 46 healthy participants with the objective to assess the effect of therapeutic (300 mg twice daily for 6 days) and supratherapeutic (750 mg twice daily for 6 days) oral doses of icenticaftor on electrocardiogram parameters, including concentration-corrected QT (QTc) analysis. Moxifloxacin (400 mg, oral) was used as a positive control. In the concentration-QTc analysis performed on pooled data from Day 1 and Day 6 (steady state), the estimated population slope was shallow and slightly negative: –0.0012 ms/ng/mL. The effect on the Fridericia corrected QT (QTcF) interval (∆ΔQTcF) was predicted to be −1.3 milliseconds at the icenticaftor 300-mg twice-daily peak concentration (geometric mean was 1094 ng/mL) and −5.5 milliseconds at the 750-mg twice-daily peak concentration (geometric mean C_max was 4529 ng/mL) indicated a mild shortening effect of icenticaftor on QTcF interval length. The results of the by-time-point analysis indicated least squares placebo corrected mean ∆∆QTcF across time points ranged from –7.9 to 0.1 milliseconds at 1 and 24 hours after dosing both on Day 6 in the 750-mg dose group compared with –3.7 to 1.6 milliseconds at 1.5 and 24 hours after dosing on Day 1 in the 300-mg dose group. Assay sensitivity was demonstrated with moxifloxacin. The large accumulation of exposures, especially the 4.3-fold increase in peak plasma concentration observed at the icenticaftor 750-mg twice-daily dosage compared with Icenticaftor 300 mg twice daily (2.3-fold) on Day 6 provided a large concentration range (up to 9540 ng/mL) to evaluate the effect of icenticaftor on ΔΔQTcF. Based on the concentration–QTc analysis, an effect on ΔΔQTcF exceeding 10 milliseconds can be excluded within the full observed ranges of plasma concentrations on icenticaftor, up to approximately 9540 ng/mL. Icenticaftor at the studied doses demonstrated a mild shortening in QTcF, which is unlikely to be of clinical relevance in a therapeutic setting.