Roxadustat, a hypoxia-inducible factor prolyl hydroxylase inhibitor, treats anemia in chronic kidney disease. Hyperphosphatemia, a common complication in chronic kidney disease, is treated with ...phosphate binders (PBs). This study in healthy individuals investigated the effect of 2 PBs, sevelamer carbonate and calcium acetate, on the pharmacokinetic properties of a single oral dose of roxadustat administered concomitantly or with a time lag.
This 2-part, Phase I study was conducted with an open-label, randomized, 3-way (part 1) or 5-way (part 2) crossover design, with 5-day treatment periods. On day 1 of each period, participants received 200 mg roxadustat administered alone or (1) concomitantly with sevelamer carbonate (2400 mg) or calcium acetate (1900 mg) (part 1) or (2) 1 hour before or 1, 2, or 3 hours after sevelamer carbonate (part 2A) or calcium acetate (part 2B); 5 additional PB doses were administered during 2 days. In both parts, PBs were administered with meals. Primary pharmacokinetic variables were AUC0–∞ and Cmax.
Twenty-four individuals were randomized in part 1; 60 individuals were randomized in part 2 (part 2A, n = 30; part 2B, n = 30). All participants completed the study in part 1; 28 and 27 individuals completed the study in part 2A and part 2B, respectively. Compared with roxadustat alone, concomitant sevelamer carbonate and calcium acetate administration reduced roxadustat's AUC0–∞ by 67% (90% CI, 63.5%–69.3%) and 46% (90% CI, 41.7%–50.9%), respectively, and reduced roxadustat's Cmax by 66% (90% CI, 61.6%–69.4%) and 52% (90% CI, 46.2%–57.2%), respectively. This effect was attenuated when roxadustat and PB administration occurred with a time lag. Roxadustat's AUC0–∞ was reduced by 41% and 22% to 25%, respectively, when roxadustat was administered 1 hour before or 1 to 3 hours after sevelamer carbonate and by 31% and 14% to 18%, respectively, when administered 1 hour before or 1 to 3 hours after calcium acetate. Roxadustat's Cmax was reduced by 26% and 12%, respectively, when roxadustat was administered 1 hour before and 1 hour after sevelamer carbonate; it was reduced by 19% when administered 1 hour before calcium acetate and was not affected when administered 1 hour after. Roxadustat was well tolerated.
Concomitant administration of roxadustat with sevelamer carbonate or calcium acetate reduced exposure to roxadustat in healthy individuals. This effect was attenuated when roxadustat was administered ≥1 hour before or after either PB. Results from this study helped inform dosing and administration guidelines aimed at reducing interactions between roxadustat and these PBs.
Background:
Pharmacokinetics, pharmacodynamics and general safety and tolerability of JNJ-42847922, a selective orexin-2 receptor antagonist, were assessed in healthy subjects.
Methods:
Five ...consecutive cohorts of healthy subjects were enrolled and received doses of 5–60 mg orally once daily over 10 days of JNJ-42847922 (n=6) or placebo (n=2). Concentrations of drug in plasma and urine were measured over 24 h after dosing on Days 1, 5 and 10. Observed- and self-reported somnolence was used to evaluate the principal pharmacodynamic effect of JNJ-42847922. A test battery to assess vigilance state, sedation and alertness was assessed at 4, 6 and 8 h after dosing. Safety assessments included recording of adverse events, vital signs, electrocardiograms, clinical laboratory assessments and suicidality per Columbia Suicide Severity Rating Scale.
Results:
JNJ-42847922 was rapidly absorbed after the morning dose administration. The median tmax ranged from 0.5–1.5 h and mean t1/2 values from 2–3 h. At JNJ-42847922 dose levels ⩾20 mg, mean Cmax and mean area under the curve, values increased less than dose proportionally. At doses ⩾20 mg, JNJ-42847922 consistently induced somnolence on all study days. At four hours post-dose administration, dose levels >5 mg JNJ-42847922 were identified as sedating by the Addiction Research Center Inventory-49. Except for a mild decrease in attention (Bond and Lader Visual Analogue Scale Factor 1) at dose levels >10 mg at four hours post-dose, no clinically relevant changes in other central measures have been observed. JNJ-42847922 was well tolerated.
Aims
SAR247799 is a selective G‐protein‐biased sphingosine‐1 phosphate receptor‐1 (S1P1) agonist with potential to restore endothelial function in vascular pathologies. SAR247799, a first‐in‐class ...molecule differentiated from previous S1P1‐desensitizing molecules developed for multiple sclerosis, can activate S1P1 without desensitization and consequent lymphopenia. The aim was to characterize SAR247799 for its safety, tolerability, pharmacokinetics and pharmacodynamics (activation and desensitization).
Methods
SAR247799 was administered orally to healthy subjects in a double‐blind, randomized, placebo‐controlled study with single (2.5–37.5 mg) or 2‐week once‐daily (0.5–15 mg) doses. An open‐label single dose pilot food‐interaction arm with 10 mg SAR247799 in cross‐over design was also performed.
Results
SAR247799 was well tolerated and, at the higher end of the dose ranges, caused the expected dose‐dependent pharmacodynamics associated with S1P1 activation (heart rate reduction) and S1P1 desensitization (lymphocyte count reduction). SAR247799 demonstrated dose‐proportional increases in exposure and was eliminated with an apparent terminal half‐life of 31.2–33.1 hours. Food had a small effect on the pharmacokinetics of SAR247799. SAR247799 had a low volume of distribution (7–23 L), indicating a potential to achieve dose separation for endothelial vs cardiac S1P1 activation pharmacology. A supratherapeutic dose (10 mg) of SAR247799 produced sustained heart rate reduction over 14 days, demonstrating cardiac S1P1 activation without tachyphylaxis. Sub‐lymphocyte‐reducing doses (≤5 mg) of SAR247799, which, based on preclinical data, are projected to activate S1P1 and exhibit endothelial‐protective properties, had minimal‐to‐no heart rate reduction and displayed no marked safety findings.
Conclusion
SAR247799 is suitable for exploring the biological role of endothelial S1P1 activation without causing receptor desensitization.
Abstract Purpose Roxadustat is a small-molecule hypoxia-inducible factor prolyl-hydroxylase inhibitor in late-stage clinical development for the treatment of anemia in patients with chronic kidney ...disease (CKD). Warfarin is an oral anticoagulant with a narrow therapeutic window that is often prescribed to treat coexisting cardiovascular diseases in patients with CKD. This clinical trial was designed to evaluate the effect of roxadustat on warfarin pharmacokinetic and pharmacodynamic parameters. Methods This open-label, single-sequence crossover study was conducted in healthy volunteers (male or female) aged 18 to 55 years with a body mass index of 18.5 to 30.0 kg/m2 . The study consisted of 2 periods separated by a minimum washout period of 14 days. After an overnight fast, volunteers received a single oral dose of 25 mg (5 × 5 mg tablets) warfarin on Day 1 of Period 1 and Day 7 of Period 2. Volunteers received oral doses of 200 mg (2 × 100 mg tablets) roxadustat on Days 1, 3, 5, 7 (concomitant with warfarin), 9, 11, 13, and 15 of Period 2. Plasma S- and R-warfarin (unbound and total concentrations) and prothrombin time were determined at multiple time points up to 216 hours postdose. Pharmacokinetic and pharmacodynamic parameters were estimated via noncompartmental methods. Tolerability was evaluated by monitoring adverse events, laboratory assays, vital signs, and 12-lead ECGs. Findings The geometric mean ratios and 90% CIs for Cmax and AUC∞ of total and unbound S- and R-warfarin (with and without roxadustat) were within the standard bioequivalence interval of 80.00% to 125.00%. Roxadustat increased the geometric mean (GM) prothrombin (PT) and international normalized ratio (INR) AUC from time zero to last measurable sample (AUCPT,last and AUCINR,last ) by 24.4%. Coadministration of roxadustat and warfarin in healthy volunteers was associated with a favorable tolerability profile, with most treatment-associated adverse events mild in severity. Implications Based on the lack of clinically significant pharmacokinetic interactions and the limited influence on warfarin pharmacodynamic parameters, no dose adjustment of warfarin should be required when coadministered with roxadustat. ClinicalTrials.gov identifier: NCT02252731.
Nilotinib (Tasigna), a highly selective and potent BCR‐ABL tyrosine kinase inhibitor (TkI), is administered orally and has pH‐dependent aqueous solubility, with lower dissolution at higher pH. This ...study evaluated the effect of esomeprazole on the pharmacokinetics of nilotinib in healthy participants. Twenty‐two participants (6 women, 16 men, mean age of 44.9 ± 12.9 years) were enrolled to receive nilotinib as a single oral 400‐mg dose on days 1 and 13 and esomeprazole as 40 mg once daily on days 8 to 13. Serial blood samples were collected up to 72 hours after nilotinib dosing, and nilotinib serum concentrations were determined by a validated liquid chromatography/ tandem mass spectrometry assay. Gastric pH was also monitored in all participants. When coadministered with esomeprazole, nilotinib Cmax was decreased by 27% and AUC0‐∞ decreased by 34%. Nilotinib tmax was prolonged from 4.0 to 6.0 hours, but t1/2 was not altered. Mean gastric pH was 1.0 ± 0.5 at baseline and increased to 2.79 ± 2.50, 3.98 ± 2.27, 5.30 ± 1.70, 5.38 ± 1.26, and 5.31 ± 1.42 at predose and 1, 2, 3, and 4 hours after the fifth esomeprazole dose, respectively. These results suggested a modest reduction in the rate and extent of nilotinib absorption by esomeprazole. Nilotinib is a TKI that may be used concurrently with esomeprazole or other proton pump inhibitors.
Background and Objectives
Roxadustat is an orally active hypoxia-inducible factor prolyl hydroxylase inhibitor for the treatment of anemia in chronic kidney disease. This study investigated the ...effect of multiple daily oral doses of omeprazole on the pharmacokinetics, safety, and tolerability of a single oral dose of roxadustat.
Methods
This phase 1, open-label, two-period, one-sequence, crossover study enrolled healthy subjects. During Period 1, subjects received a single oral dose of 100 mg roxadustat. After a ≥ 7-day washout, subjects started Period 2 and received daily oral doses of 40 mg omeprazole on Days 1–9, and a single oral dose of 100 mg roxadustat on Day 7. Roxadustat pharmacokinetics were assessed on Days 1–4 in Period 1 and on Days 7–10 in Period 2. Primary endpoints were area under the concentration–time profile from the time of dosing extrapolated to infinity (AUC
inf
) and maximum concentration (C
max
). Safety was assessed by vital signs, laboratory tests, electrocardiograms, and nature, frequency, and severity of treatment-emergent adverse events (TEAEs).
Results
Eighteen subjects were enrolled. The geometric least squares mean ratio for both AUC
inf
and C
max
of roxadustat (with omeprazole/alone) was 104.5%; 90% confidence intervals were within the no-effect boundaries of 80.0 and 125.0%, indicating no significant effect of omeprazole on the pharmacokinetics of roxadustat. No serious TEAEs were reported.
Conclusion
Multiple daily oral doses of 40 mg omeprazole had no significant effect on the pharmacokinetics of a single oral dose of 100 mg roxadustat. Roxadustat was considered safe and well tolerated when administered alone or in combination with multiple daily oral doses of 40 mg omeprazole in healthy subjects.
Pasireotide (SOM230) is a multireceptor-targeted somatostatin analog with high binding affinity for four of the five somatostatin receptor subtypes (sst(1,2,3) and sst(5)), and potential clinical ...activity in several neuroendocrine and oncologic conditions, including acromegaly, Cushing's disease, and neuroendocrine tumors (NET). This manuscript reports the first-in-man dose-escalation study of pasireotide, evaluating its safety, tolerability, and pharmacokinetics (PK) in healthy male volunteers. A single dose of pasireotide 1-1200 μg was administered subcutaneously in four to eight subjects per dose level, with two additional subjects per cohort administered placebo. PK and safety evaluations were carried out over 7 days post-dose. Growth hormone (GH) suppression was evaluated using a GH-releasing hormone stimulation test on Day -1 and Day 1 at 3-5 hours post-injection. Seventy-two subjects completed the study. Pasireotide was well tolerated with no serious adverse events observed at any dose. Transient elevations in blood glucose levels were observed 2-6 hours after administration of pasireotide at doses between 200 μg and 1200 μg, but this resolved without intervention by 23 hours post-dosing. The maximum tolerable dose was not established within the tested range. Pasireotide demonstrated a favorable PK profile with fast absorption (t(max): 0.25-0.5 hours), low clearance (CL/F: 8-13 L/hour), long effective elimination half-life (mean t(½,β): 7-11 hours), and a proportional dose-exposure relationship. GH suppression of 79%-96% was observed at single pasireotide doses between 200 μg and 1200 μg. In conclusion, pasireotide demonstrated favorable safety, tolerability, and PK profiles, as well as promising activity in suppressing the release of GH. The efficacy and safety of pasireotide is currently being evaluated in patients with acromegaly, Cushing's disease, NET, and various non-neuroendocrine disorders.
Introduction. This randomized, double-blind, placebo-controlled, ascending-dose study was conducted in healthy volunteers to evaluate the safety of the investigational cyanide antidote ...hydroxocobalamin. Methods. Four ascending dosing groups received intravenous doses of 2.5, 5, 7.5 or 10 g hydroxocobalamin over 7.5 to 30 minutes at a constant infusion rate. Volunteers (n = 136) randomized 3:1 to receive hydroxocobalamin or placebo underwent a 4-day in-house observation after infusion on Day 1 and follow-up visits on Days 8, 15, and 28. Results. The most common drug-related adverse events were asymptomatic and self-limiting chromaturia and reddening of the skin, which are attributed to the red color of hydroxocobalamin. Other adverse events included pustular/papular rash, headache, erythema at the injection site, decrease in lymphocyte percentage, nausea, pruritus, chest discomfort, and dysphagia. Hydroxocobalamin was associated with an increase in blood pressure in some volunteers. Blood pressure changes peaked toward the end of hydroxocobalamin infusion and typically returned to baseline levels by 4 hours postinfusion. Maximum mean changes from baseline in systolic blood pressure ranged from 22.6 to 27.0 mmHg across hydroxocobalamin doses compared with 0.2 to 6.7 mmHg in the corresponding placebo groups. Maximum mean change from baseline in diastolic blood pressure ranged from 14.3 to 25.4 mmHg across hydroxocobalamin doses compared with −3.0 to 3.8 mmHg in the corresponding placebo groups. Two allergic reactions that occurred within minutes after start of the 5- and 10-g hydroxocobalamin infusions were successfully managed with dexamethasone and/or dimethindene maleate. Conclusion. Timely intervention for acute cyanide poisoning could entail administration of an antidote in the prehospital setting based on a presumptive diagnosis. Results of this placebo-controlled study in healthy volunteers corroborate previous studies and French postmarketing experience in cyanide-exposed patients in suggesting that the safety profile of hydroxocobalamin is consistent with prehospital or hospital use.
Interleukin‐6 (IL‐6) is implicated in the pathophysiology of several inflammatory conditions. Olokizumab, a humanized anti‐IL‐6 monoclonal antibody, selectively blocks the final assembly of the IL‐6 ...signaling complex. A randomized, double‐blind, placebo‐controlled, phase I dose‐escalation study assessed the safety and tolerability of escalating single doses of olokizumab administered intravenously (iv) or subcutaneously (sc) to 67 healthy male volunteers. The pharmacokinetics, pharmacodynamics and immunogenicity of olokizumab were also assessed. Olokizumab was tolerated at doses up to 3.0 mg/kg sc and 10.0 mg/kg iv; the maximum tolerated dose was not reached. No serious adverse events or withdrawals as a result of treatment‐emergent adverse events were reported. Pharmacokinetic analysis showed that both maximum serum concentration and area under the concentration–time curve increased linearly with increasing dose. Mean terminal half‐life was 31.5 days (standard deviation 12.4 days). The bioavailability of the sc doses ranged from 84.2% to 92.5%. Rapid decreases in C‐reactive protein concentrations were observed, with no dose dependency.
Compounds that selectively target orexin-1 receptors may be beneficial for the treatment of various disorders. The role of selective orexin-1 receptor antagonists (1-SORAs) in addictive behavior and ...stress/anxiety-related disturbances has been demonstrated in animals. ACT-539313, an orally active, potent 1-SORA, has been assessed in a clinical single-ascending dose study and exhibited good safety and tolerability. In the two reported studies on ACT-539313, multiple-dose pharmacokinetics (PK), pharmacodynamics (PD), safety, and tolerability were investigated and in a proof-of-mechanism study a CO2 challenge was applied as pharmacological model for induction of anxiety and panic symptoms (sequential inhalation of air, 7.5% CO2, and 35% CO2).
Two double-blind, placebo-controlled, randomized, multiple-dose studies included 58 healthy male and female subjects. In Study 1, multiple-ascending oral doses of 30, 100, and 200 mg twice daily (b.i.d.) ACT-539313 were investigated in 3 dose groups of 8 or 12 subjects (of whom 2 received placebo per dose group). Study 2 was conducted as a randomized two-way crossover design, enrolling 21 male and 9 female subjects who received 200 mg ACT-539313 or matching placebo b.i.d. for 2.5 days followed by a CO2 challenge, with a washout period in between. PK, PD (objective and subjective measures of sedation, alertness, effects on central nervous system (CNS), and anxiety/panic symptoms), safety, and tolerability were assessed.
At steady state, ACT-539313 was rapidly absorbed with a median time to maximum plasma concentration of 1.8–2.3 h and eliminated with a mean half-life of 3.8–6.5 h. Overall exposure increased dose-proportionally. In Study 1, PD effects confirmed activity of ACT-539313 on the CNS, without consistent or marked effects of sedation, reduced alertness or visuo-motor impairment. In the CO2 challenge, cortisol concentrations were lower during initial air inhalation after treatment with ACT-539313 compared to placebo, while no difference was detected after CO2 inhalation. Trends for lower scores in subjective anxiety assessments were observed for ACT-539313. Besides reports of stress related to the challenge, the most frequently reported adverse events were somnolence and headache. No clinically relevant effects in other safety assessments were observed.
Multiple-dose administration of ACT-539313 was safe and well tolerated up to multiple doses of 200 mg b.i.d. The drug's PK properties as well as the pattern of a decrease in stress-related symptoms after the CO2 challenge support further investigations of ACT-539313.
•The orally available orexin-1 receptor antagonist ACT-539313 could provide a new treatment modality for a variety of neurological and psychiatric disorders that present with abnormal arousal states, anxiety-related symptoms, and exaggerated reactions to external cues.•ACT-539313 exhibits good safety and tolerability after multiple doses in healthy subjects up to 200 mg b.i.d.•The terminal half-life of ACT-539313 was 3.8–6.5 h across dose levels.•AUC0-τ increased approximately dose-proportionally and Cmax less than dose-proportionally.•ACT-539313 showed trends for lower anxiety scores in the CO2 challenge, a pharmacological model for induction of anxiety and panic symptoms.
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