Phase 1, randomized, crossover study comparing intravenous GTX-104 to oral nimodipine in healthy human subjects

Intranasal (i.n.) naloxone is an established treatment for opioid overdose. Anyone likely to witness an overdose should have access to the antidote. We aimed to determine whether an i.n. formulation delivering 1.4mg naloxone hydrochloride would achieve systemic exposure comparable to that of 0.8mg intramuscular (i.m.) naloxone. Open, randomized four-way cross-over trial. Clinical Trials Units in St Olav's Hospital, Trondheim and Rikshospitalet, Oslo, Norway. Twenty-two healthy human volunteers, 10 women, median age=25.8years. One and two doses of i.n. 1.4mg naloxone compared with i.m. 0.8mg and intravenous (i.v.) 0.4mg naloxone. Quantification of plasma naloxone was performed by liquid chromatography tandem mass spectrometry. Pharmacokinetic non-compartment analyses were used for the main analyses. A non-parametric pharmacokinetic population model was developed for Monte Carlo simulations of different dosing scenarios. Area under the curve from administration to last measured concentration (AUC0-last ) for i.n. 1.4mg and i.m. 0.8mg were 2.62±0.94 and 3.09±0.64h×ng/ml, respectively (P=0.33). Maximum concentration (Cmax ) was 2.36±0.68ng/ml for i.n. 1.4mg and 3.73±3.34 for i.m. 0.8mg (P=0.72). Two i.n. doses showed dose linearity and achieved a Cmax of 4.18±1.53ng/ml. Tmax was reached after 20.2±9.4minutes for i.n. 1.4mg and 13.6±15.4minutes for i.m. 0.8 mg (P=0.098). The absolute bioavailability for i.n. 1.4mg was 0.49 (±0.24), while the relative i.n./i.m. bioavailability was 0.52 (±0.25). Intranasal 1.4mg naloxone provides adequate systemic concentrations to treat opioid overdose compared with intramuscular 0.8mg, without statistical difference on maximum plasma concentration, time to maximum plasma concentration or area under the curve. Simulations support its appropriateness both as peer administered antidote and for titration of treatment by professionals.

Background and ObjectivePL8177 is a selective melanocortin 1 receptor agonist in development for the treatment of various immunologic and inflammatory conditions. Here we describe the pharmacokinetics of PL8177 after subcutaneous (sc) delivery in animals and humans.MethodsMice, rats, and dogs were administered sc PL8177 at single doses of 1.0 and 3.0 mg/kg (mice); 1.0, 5.0, and 25.0 mg/kg/day (rats); or 1.5, 8.0, and 40.0 mg/day (dogs). Blood was collected over 24 h (mice) or 28 days (rats and dogs). Safety and pharmacokinetics of single and multiple sc doses were also examined in human volunteers. Two dose levels were tested in two dosing cohorts of 1.0 and 3.0 mg/day for 7 days. Blood samples were collected through Day 1 and on Days 2 to 6 at peak and trough times based on analysis of the first two single-dose cohorts.ResultsIn mice, 3 mg/kg PL8177 resulted in an area under the plasma concentration–time curve from 0 to infinity (AUC∞) of 1727 ng·h/mL, a maximum plasma concentration (Cmax) of 2440 ng/mL, an elimination half-life (t½) of 0.5 h, and a time to maximum concentration (tmax) of 0.25 h. Results for the 1-mg/kg dose were generally proportional. In rats, mean tmax values were independent of dose and ranged from 0.25 to 1.0 h for single and multiple dosing. Cmax values ranged from 516 to 695 ng/mL (1-mg/kg dose) and from 666 to 1180 ng/mL (25-mg/kg dose). In dogs, mean tmax values ranged from 0.4 to 1.3 h for single and multiple dosing. Values for tmax decreased with increasing dose and mean plasma Cmax increased less than dose proportionally (96–129 ng·h/mL [1.5 mg], 275–615 ng·h/mL [8.0 mg], and 633–1280 ng·h/mL [40.0 mg]). In humans, PL8177 was observed in the plasma within 15 min after a single dose and persisted for up to 48 h at higher doses. The tmax was 30–45 min (single dose) and 15–45 min (multiple doses). In multiple-dose studies, maximum steady-state plasma concentration (Cmax,ss) and AUC∞ increased with dose. Geometric mean Cmax,ss values were 20.1 ng/mL (1.0 mg) and 57.2 ng/mL (3.0 mg). AUC∞ values were 54.3 ng·h/mL (1.0 mg) and 199 ng·h/mL (3.0 mg). Unchanged PL8177 excreted in the urine was ≤ 1%, and accumulation was minimal.ConclusionPL8177 administration resulted in a consistent pharmacokinetic profile. The measured exposure levels resulted in pharmacologically active PL8177 concentrations at the targeted MC1R. Rapid absorption was seen in healthy volunteers, and multiple-dose administration over 7 days resulted in pharmacokinetic characteristics similar to those observed after single-dose administration. Results support the continued development of PL8177 to treat immunologic and inflammatory conditions.

Early recognition of vasospasm (VS) in patients with aneurismal subarachnoid hemorrhage (aSAH) is an imperative for timely treatment and prevention of delayed cerebral ischemia (DCI). VS, the pathologic response of the vascular damage in aSAH, is the main risk factor for irreversible brain damage. The first step in successful solving of aneurismal bleeding is prevention and treatment of VS. The aim of this study is to determine whether medical treatment with continuous infusion of intravenous Calcium blocker Nimodipine, without radiology verified VS will impact the degree of arterial vasoconstriction during the endovascular aneurismal treatment (EVT). A total of 20 patients with aSAH, confirmed by CT-angiography and hospitalized in UC for Neurosurgery were included in the study. In 10 patients, a continuous iv Nimodipine infusion was initiated on admission, the other half remained on their own antihypertensive therapy. If signs of VS or neurologic deterioration had developed, iv vasodilator therapy would have been initiated. Control angiography and immediate EVT were performed on the 4th day of admission at Radiology Institute. Using angiography, the vascular diameter was measured and compared with the same vessel diameter on CTA, to determine whether iv Nimodipine is effective in the pretreatment period. In 8 of 10 treated patients with iv Nimodipine, VS resolved in preEVT period. Among the patients from the non-treated group, 1 had developed DCI, 1 had no VS, 6 had persistent and in 2 patients VS resolved spontaneously. The conclusion is that continuous iv Nimodipine in preEVT period has vasodilatory potency on the vascular pool. Key words: Aneurismal subarachnoid hemorrhage, vasospasm, intravenous Nimodipine, endovascular treatment

Oral nimodipine is the only drug approved in North America for patients with aneurysmal subarachnoid hemorrhage (aSAH). However, bioavailability is variable and frequently poor, leading to fluctuations in peak plasma concentrations that cause dose-limiting hypotension. Furthermore, administration is problematic in patients who cannot swallow. An oral liquid formulation exists but causes diarrhea. An intravenous nimodipine formulation (GTX-104) has been developed that has bioavailability approaching 100% and is not affected by feeding or gastrointestinal absorption. GTX-104 causes less hypotension and has more consistent peak plasma concentrations than oral nimodipine in human volunteers. Herein, we describe the protocol of a prospective, randomized, open-label safety, and tolerability study of GTX-104 compared with oral nimodipine in patients with aSAH (Safety and Tolerability of GTX-104 [Nimodipine Injection for Intravenous Infusion] Compared with Oral Nimodipine; ClinicalTrials.gov identifier: NCT05995405). The study is designed to seek approval of GTX-104 by the Food and Drug Administration 505(b)(2) pathway. Inclusion and exclusion criteria match the prescribing information for oral nimodipine and include adult patients with aSAH of all Hunt and Hess grades who can receive investigational product within 96 h of aSAH. Study participants at imminent risk of death will be excluded. Study participants will be randomly assigned 1:1 to receive GTX-104 or oral nimodipine for up to 21 days. The primary end point is the proportion of study participants with clinically significant hypotension, defined as hypotension requiring treatment that has a reasonable likelihood of being due to investigational product as determined by an independent, blinded end point adjudication committee. No statistical analysis of the end point is planned. Secondary end points include all episodes of hypotension, all adverse events, delayed cerebral ischemia, rescue therapy, and suicidal ideation. Clinical and health economic outcomes include quality of life using the EuroQol 5-dimension/3-level, modified Rankin Scale score at 30 and 90 days after aSAH and hospital resource use. The planned sample size is 100 study participants across 25 sites in the United States and Canada.

The pharmacokinetics and suction-induced blister fluid penetration of cefdinir following single oral administrations of 200, 300, 400, and 600 mg were studied in 16 healthy young male volunteers according to a Latin square design. Plasma, blister, and urine samples were assayed by high-pressure liquid chromatography. We observed a nonlinear relationship (P = 0.02) between the dose and the maximum concentration in plasma as well as between the dose and the area under the concentration-time curve (AUC) in plasma (P < 0.001), which may be indicative of a limited absorption process. This resulted in a lower AUC value than expected as well as a smaller fraction of cefdinir excreted unchanged at a dose of 600 mg. Renal clearance decreased with increasing doses (P < 0.006; analysis of variance with the Latin square design and Games-Howell procedure). Maximal cefdinir concentrations in blister fluid were delayed compared with concentrations in plasma. Blister fluid penetration measured by the ratio of the AUC in blister fluid to the AUC in plasma was extensive (92.4 to 108.4%). Cefdinir concentrations in blister fluid remained equal to or higher than the concentrations in plasma from 6 to 12 h following cefdinir administration. On the basis of the concentrations in blister fluid and the in vitro MIC data, we estimated that cefdinir at 200 to 400 mg administered twice daily would be adequate to treat uncomplicated skin infections caused by Streptococcus pyogenes. Seven volunteers experienced episodes of light-to-moderate diarrhea. These adverse events occurred irrespective of dose.

Ischemic complications account for significant patient morbidity following aneurysmal subarachnoid hemorrhage (aSAH). The Prevention and Treatment of Vasospasm with Clazosentan (REACT) study was designed to assess the safety and efficacy of clazosentan, an endothelin receptor antagonist, in preventing clinical deterioration due to delayed cerebral ischemia (DCI) in patients with aSAH. REACT was a prospective, multicenter, randomized, double-blind, phase 3 study. Eligible patients had aSAH secured by surgical clipping or endovascular coiling, and had presented with thick and diffuse clot on admission CT scan. Patients were randomized (1:1 ratio) to 15 mg/hour intravenous clazosentan or placebo within 96 hours of the aSAH for up to 14 days, in addition to standard of care treatment including oral or intravenous nimodipine. The primary efficacy endpoint was the occurrence of clinical deterioration due to DCI up to 14 days after initiation of the study drug. The main secondary endpoint was the occurrence of clinically relevant cerebral infarction at day 16 after study drug initiation. Other secondary endpoints included clinical outcome assessed on the modified Rankin Scale (mRS) and the Glasgow Outcome Scale-Extended (GOSE) at week 12 post-aSAH. Imaging and clinical endpoints were centrally adjudicated. A total of 409 patients were randomized between February 2019 and May 2022 across 74 international sites. Three patients did not start study treatment and were not included in the analysis set. The occurrence of clinical deterioration due to DCI was 15.8% (32/202 patients) in the clazosentan group and 17.2% (35/204 patients) in the placebo group, and the difference was not statistically significant (relative risk reduction [RRR] 7.2%, 95% CI -42.6% to 39.6%, p = 0.734). A nonsignificant RRR of 34.1% (95% CI -21.3% to 64.2%, p = 0.177) was observed in clinically relevant cerebral infarcts treated with clazosentan (7.4%, 15/202) versus placebo (11.3%, 23/204). Rescue therapy was less frequently needed for patients treated with clazosentan compared to placebo (10.4%, 21/202 vs 18.1%, 37/204; RRR 42.6%, 95% CI 5.4%-65.2%). A nonsignificant relative risk increase of 25.4% (95% CI -10.7% to 76.0%, p = 0.198) was reported in the risk of poor GOSE and mRS scores with clazosentan (24.8%, 50/202) versus placebo (20.1%, 41/204) at week 12 post-aSAH. Treatment-emergent adverse events were similar to those reported previously. Clazosentan administered for up to 14 days at 15 mg/hour had no significant effect on the occurrence of clinical deterioration due to DCI. Clinical trial registration no.: NCT03585270 (ClinicalTrials.gov) EU clinical trial registration no.: 2018-000241-39 (clinicaltrialsregister.eu).

Delayed cerebral ischaemia is a significant contributor to poor outcome (death or disability) in patients with aneurysmal subarachnoid haemorrhage (SAH). Tirilazad is considered to have neuroprotective properties in animal models of acute cerebral ischaemia. To assess the efficacy and safety of tirilazad in patients with aneurysmal SAH. We searched the Cochrane Stroke Group Trials Register (last searched October 2009); the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 2, 2009); MEDLINE (1966 to October 2009); EMBASE (1980 to October 2009); and the Stroke Trials Directory, the National Center for Complementary and Alternative Medicine, and the National Institute of Health Clinical Trials Database (searched October 2009). We handsearched 10 Chinese journals, searched the reference lists of relevant publications, and contacted the manufacturers of tirilazad. Randomised trials of tirilazad started within four days of SAH onset, compared with placebo or open control in patients with aneurysmal SAH documented by angiography and computerised tomography (CT) scan or cerebrospinal fluid examination, or both. We extracted data relating to case fatality, poor outcome (death, vegetative state, or severe disability), delayed cerebral ischaemia (or symptomatic vasospasm), cerebral infarction and adverse events of treatments. We pooled the data using the Peto fixed-effect method for dichotomous data. We included five double-blind, placebo-controlled trials involving 3821 patients; there was no significant heterogeneity. Oral or intravenous nimodipine was used routinely as a background treatment in both groups in all trials. There was no significant difference between the two groups at the end of follow up for the primary outcome, death (odds ratio (OR) 0.89, 95% confidence interval (CI) 0.74 to 1.06), or in poor outcome (death, vegetative state or severe disability) (OR 1.04, 95% CI 0.90 to 1.21). During the treatment period, fewer patients developed delayed cerebral ischaemia in the tirilazad group than in the control group (OR 0.80, 95% CI 0.69 to 0.93). Subgroup analyses did not demonstrate any significant difference in effects of tirilazad on clinical outcomes. Leukocytosis and prolongation of Q-T interval occurred significantly more frequently in the treatment group in only one trial evaluating tirilazad at high dose. There was no significant difference in infusion site disorders or other laboratory parameters between the two groups. There is no evidence that tirilazad, in addition to nimodipine, reduces mortality or improves poor outcome in patients with aneurysmal SAH.

Tetramethylpyrazine nitrone (TBN) is a novel tetramethylpyrazine derivative armed with a strong free radical scavenging nitrone moiety. This study aims to evaluate the pharmacokinetics, safety profile, and tolerability of TBN tablets after a single ascending dose (SAD) and multiple ascending doses (MAD) in healthy Chinese volunteers. This phase I, single-center, open-label study was conducted in China. The SAD portion consisted of four cohorts with dose levels of 400-1800 mg. The MAD portion included three cohorts in which subjects received doses of 600-1800 mg twice daily for 7 days (13 consecutive doses). The third portion was a randomized, two-period, crossover design to assess the influence of food with a single dose of TBN tablets (1200 mg). The safety profile was evaluated by monitoring adverse events (AEs), vital signs, electrocardiograms, physical examinations, and laboratory test results. Fifty-two healthy subjects aged 18 to 45 years with a body mass index between 19.0 and 26.0 kg/m2 were enrolled. After a single dose of TBN, the median time to maximum plasma concentration (Tmax) was 2.48-3.24 h and the mean half-life (t1/2) was 1.28 to 2.10 h across all doses. In the MAD study, the median Tmax was 2.48 to 3.48 h. In the 400-1800mg dose range, there was a tendency for less than proportional increases in the maximum plasma concentration (Cmax), the area under the concentration-time curve from 0 to time of last measurable concentration (AUC0-t), and the area under the concentration-time curve from 0 to infinity (AUC0-inf) in both single- and multiple-dose periods. A significantly higher TBN exposure was observed in females than males in both a single and multiple doses of the 600mg and 1200mg groups, with a geometric mean female-to-male ratio of 138.69-203.18%. Food decreased the Cmax and AUC0-t of TBN to 45.19% and 59.73%, respectively. Each dose group reached a steady state after 4 days. No drug accumulation was observed. Two subjects had drug-related AEs. A decreased neutrophil count and drug eruption in the SAD portion (1200mg group) and an increased alanine aminotransferase level in the food effect group were found. All AEs were mild and tolerable (CTCAE grade 1) and resolved without any medical intervention. TBN tablets had a good safety profile and were well tolerated in healthy Chinese volunteers. Steady-state concentrations were reached after 4 consecutive days of oral administration. The results of this phase I study will provide guidance for the design of future TBN clinical studies. ChiCTR1900022092.

An open-label, randomized, three-way crossover trial of the effects of coadministration of rosuvastatin and fenofibrate on the pharmacokinetic properties of rosuvastatin and fenofibric acid in healthy male volunteers

Rupture of an intracranial aneurysm causes bleeding into the subarachnoid space, which may lead to spasm of the cerebral arteries and ischaemic damage to the brain. Prophylactic use of calcium antagonists in patients with ruptured intracranial aneurysms might reduce the risk of ischaemic damage. This review aimed to determine whether calcium antagonists improve outcome in patients with aneurysmal subarachnoid haemorrhage (SAH). The Cochrane Stroke Group trials register (last searched: March 1999) plus hand searching and personal contacts with trialists and pharmaceutical companies marketing calcium antagonists. All completed, unconfounded, truly randomised controlled trials comparing any calcium antagonist with control, within ten days of SAH onset. Eleven trials that met the inclusion criteria were included in the overview. Two reviewers independently extracted data and assessed trial quality. Trialists were contacted to obtain missing information. We analysed 11 trials totalling 2804 randomized patients with subarachnoid haemorrhage (1376 in the treatment and 1428 in the control group). The drugs analyzed were: nimodipine (eight trials, 1574 patients), nicardipine (two trials, 954 patients), and AT877 (one trial, 276 patients). In 92% of the patients aneurysms were confirmed by angiography or autopsy. Overall, calcium antagonists significantly reduce the risk of poor outcome after subarachnoid haemorrhage: relative risk (RR) 0.82 (95% CI 0. 72-0.93); the absolute risk reduction was 5.1%, the corresponding number of patients needed to treat to prevent a single poor outcome event is 20. For oral nimodipine alone the RR was 0.69 (0.58-0.84). The RR of death on treatment with calcium antagonists was 0.94 (95% CI 0.80-1.10), that of ischaemic neurological deficits 0.67 (95% CI 0.59-0.76), and that of CT-scan documented cerebral infarction 0.80 (95% CI 0.71-0.89). Calcium antagonists reduce the proportion of patients with poor outcome and ischemic neurological deficits after aneurysmal SAH; the risk reduction for case fatality alone is not statistically significant. The results for 'poor outcome' are statistically robust, but depend mainly on trials with oral nimodipine; the evidence for nicardipine and AT877 is inconclusive. The intermediate factors through which nimodipine exerts its beneficial effect after aneurysmal SAH remain uncertain.

In this review, we describe the absorption rates (Caco-2 cell permeability) and hepatic/plasma pharmacokinetics of 53 diverse chemicals estimated by modeling virtual oral administration in rats. To ensure that a broad range of chemical structures is present among the selected substances, the properties described by 196 chemical descriptors in a chemoinformatics tool were calculated for 50,000 randomly selected molecules in the original chemical space. To allow visualization, the resulting chemical space was projected onto a two-dimensional plane using generative topographic mapping. The calculated absorbance rates of the chemicals based on cell permeability studies were found to be inversely correlated to the no-observed-effect levels for hepatoxicity after oral administration, as obtained from the Hazard Evaluation Support System Integrated Platform in Japan (r = −0.88, p < 0.01, n = 27). The maximum plasma concentrations and the areas under the concentration-time curves (AUC) of a varied selection of chemicals were estimated using two different methods: simple one-compartment models (i.e., high-throughput toxicokinetic models) and simplified physiologically based pharmacokinetic (PBPK) modeling consisting of chemical receptor (gut), metabolizing (liver), and central (main) compartments. The results obtained from the two methods were consistent. Although the maximum concentrations and AUC values of the 53 chemicals roughly correlated in the liver and plasma, inconsistencies were apparent between empirically measured concentrations and the PBPK-modeled levels. The lowest-observed-effect levels and the virtual hepatic AUC values obtained using PBPK models were inversely correlated (r = −0.78, p < 0.05, n = 7). The present simplified PBPK models could estimate the relationships between hepatic/plasma concentrations and oral doses of general chemicals using both forward and reverse dosimetry. These methods are therefore valuable for estimating hepatotoxicity.

Human respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract infection, especially in children and older people. However, no effective treatment is currently available. TypeI interferons (IFNs) are a group of cytokines that help regulate the activity of the immune system. GB05, human IFNα1b inhalation solution, was developed under US Food and Drug Administration (FDA) standard guidelines to combat RSV infection. This randomized, double-blind, placebo-controlled, dose-escalation phaseI trial evaluated the safety, tolerability, and pharmacokinetics of nebulized GB05. A total of 35 eligible healthy Chinese adult volunteers were enrolled in this study. In the single ascending dose (SAD) study, volunteers were randomized into 0.2, 0.6, 1.2, and 1.8million IU of GB05 or placebo. In the multiple ascending dose (MAD) study, volunteers received 1.2 or 1.8million IU of GB05 or placebo for four consecutive days. Safety, tolerability, immunogenicity, and plasma pharmacokinetics were assessed for all groups. All adverse events were mild or moderate and resolved spontaneously. The most common adverse event was decreased white blood cell count (8.6% in SAD and 10% in MAD). No serious adverse events, deaths, or adverse events that reached the termination criteria occurred during the study. In SAD, the maximum concentration and area under the curve increased across the dose range of 1.2-1.8million IU in a non-linear relationship. The maximum plasma concentration after GB05 nebulization (1.06IU/ml in the 1.8million IU group) reflected a low concentration in the blood, suggesting a better lung uptake of GB05 and reduced incidence or risks of adverse events. In MAD, a steady state was reached after continuous administrations of twice daily for 3days. Overall, nebulized GB05 exhibited satisfactory safety, tolerability, and favorable pharmacokinetic (PK) profiles in healthy adult volunteers, supporting further clinical investigation in patients infected with respiratory syncytial virus. ClinicalTrials.gov Identifier NCT06277167.

Background and ObjectiveA novel tiotropium bromide monodose capsule dry powder inhaler (DPI) formulation and device have been developed. The formulation was based on a spray-dried matrix that enhances the aerosolizaton properties, allowing a less active tiotropium metered dose (13 µg/capsule) while maintaining the same delivered dose (10 µg/actuation). This study describes the pharmacokinetic bioequivalence to the reference product.MethodsThis randomized, two-stage, crossover, semi-replicate (three-way) study was performed in healthy volunteers. In each study period, subjects received a single dose of two capsules (20 μg delivered dose) of the study medication, separated by a 14-day washout period: tiotropium 10 μg delivered dose (Laboratorios Liconsa, Spain) and Spiriva HandiHaler® (Boehringer Ingelheim Pharma GmbH & Co KG, Germany). Blood samples were obtained up to 48 h post-dose to evaluate the comparative bioavailability. Tiotropium was measured in plasma by means of dual stage liquid–liquid extraction followed by the two-dimensional ultra-high performance liquid chromatography sensitive sub-pg/mL bioanalytical method. The main pharmacokinetic parameters were maximum plasma concentration (Cmax), area under the concentration–time curve (AUC) from time zero hours to the last observed concentration at time t (AUCt), and AUC from time zero hours to 30 min (AUC0.5). Bioequivalence was accepted if the 90.20 % confidence interval (CI) for the ratio test/reference of the primary pharmacokinetic parameters lay within the acceptance range of 80–125 %. Safety assessment was a secondary endpoint.ResultsA total of 30 subjects were randomized and bioequivalence was demonstrated for all primary pharmacokinetic parameters: Cmax (CI 87.26–106.60 %), AUCt (CI 101.33–111.64 %), and AUC0.5 (CI 97.95–113.49 %). Both study treatments were well tolerated (four non-serious adverse events [AEs] were reported in four subjects: one AE before any product administration, two AEs after test product administration; and one AE after reference product administration).ConclusionsBoth products containing tiotropium 10 µg delivered-dose DPI were bioequivalent and showed good tolerability and a similar safety profile.

Elagolix is an oral, non-peptide, gonadotropin-releasing hormone receptor antagonist. It is approved for the treatment of moderate-to-severe pain associated with endometriosis and is being investigated for the treatment of heavy menstrual bleeding associated with uterine fibroids. Use of low-dose hormonal add-back therapy can reduce hypoestrogenic effects associated with elagolix, thus there is a need to determine if there is a pharmacokinetic interaction between elagolix and low-dose hormonal add-back therapy. Two multiple-dose, open-label, single-sequence, non-randomized studies for elagolix 300mg twice daily with oral (n = 24) and transdermal (n = 36) low-dose add-back therapy (estradiol [E2]/norethindrone acetate [NETA]; 1mg/0.5mg oral and 0.51mg/4.8mg transdermal) in healthy postmenopausal women were conducted, with pharmacokinetic sampling for E2, estrone (E1), and NETA up to 72 or 96h after dosing. Pharmacokinetic parameters for hormones were estimated using noncompartmental methods. No change in norethindrone maximum plasma concentration or area under the concentration-time curve was observed when oral E2/NETA was administered with elagolix. For E2, there was a 2-fold increase in maximum plasma concentration and a 1.5-fold increase in the area under the concentration-time curve, and for E1 there was a 1.7-fold increase in maximum plasma concentration when oral E2/NETA was administered with elagolix. Exposures for norethindrone, E2, and E1 were unchanged when transdermal E2/NETA was applied with elagolix administration. Although changes in E2/E1 exposures were observed when oral E2/NETA was co-administered with elagolix, these changes are not considered clinically relevant; and no dose adjustments are recommended when elagolix is co-administered with oral or transdermal low-dose add-back therapy.

The effect of two different meals on the bioavailability of nilvadipine, a new antihypertensive and antianginal drug, was examined in 16 healthy male volunteers in two separate studies. In each study of eight subjects in a Latin-square, two-way crossover design, two groups of four subjects each were given a single 6-mg oral dose of nilvadipine after overnight fasting or 30 minutes after a 464- or 748-kcal meal. There were no significant differences in the area under the plasma concentration-time curve or the maximum plasma concentration between the fasting and fed states for either meal. Although the time to reach the maximum plasma concentration was about the same after a 464-kcal meal and after fasting, it increased slightly but significantly after a 748-kcal meal, indicating possible delay in drug absorption after meals. These studies showed that the extent of bioavailability of nilvadipine appears to be little affected in the presence of food. Although a possible delay in the onset of absorption would occur, such a delay may not have any therapeutic importance in chronic therapy.