Pharmacokinetics of the Antimalarial Drug, AQ-13, in Rats and Cynomolgus                Macaques

The purpose of this study was to evaluate the bioavailability and pharmacokinetics of a new antimalarial drug, AQ-13, a structural analog of chloroquine (CQ) that is active against CQ-resistant Plasmodium species, in rats and cynomolgus macaques. Sprague-Dawley rats ( n = 4 /sex) were administered a single dose of AQ-13 intravenously (i.v.) (10 mg/kg) or orally (20 or 102 mg/kg). Blood and plasma samples were collected at several timepoints. AQ-13 achieved Cmax after oral administration at approximately 3 to 4 h and could be detected in blood for 2 to 5 days after oral administration. The ratio of area under the curve (AUC) values at the high and low dose for AQ-13 deviated from an expected ratio of 5.0, indicating nonlinear kinetics. A metabolite peak was noted in the chromatograms that was identified as monodesethyl AQ-13. Oral bioavailability of AQ-13 was good, approximately 70%. The pharmacokinetics of AQ-13 was also determined in cynomolgus macaques after single (i.v., 10 mg/kg; oral, 20 or 100 mg/kg) and multiple doses (oral loading dose of 50, 100, or 200 mg/kg on first day followed by oral maintenance dose of 25, 50, or 100 mg/kg, respectively, for 6 days). The AUC and Cmax values following single oral dose administration were not dose proportional; the Cmax value for AQ-13 was 15-fold higher following an oral dose of 100 mg/kg compared to 20 mg/kg. MonodesethylAQ-13 was a significant metabolite formed by cynomolgus macaques and the corresponding Cmax values for this metabolite increased only 3.8-fold over the dose range, suggesting that the formation of monodesethyl AQ-13 is saturable in this species. The bioavailability of AQ-13 in cynomolgus macaques following oral administration was 23.8% for the 20-mg/kg group and 47.6% for the 100-mg/kg group. Following repeat dose administration, high concentrations of monodesethyl AQ-13 were observed in the blood by day 4, exceeding the AQ-13 blood concentrations through day 22. Saturation of metabolic pathways and reduced metabolite elimination after higher doses are suggested to play a key role in AQ-13 pharmacokinetics in macaques. In summary, the pharmacokinetic profile and metabolism ofAQ-13 are very similar to that reported in the literature for chloroquine, suggesting that this new agent is a promising candidate for further development for the treatment of chloroquine-resistant malaria.

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Pharmacokinetics of Ferroquine, a Novel 4-Aminoquinoline, in Asymptomatic Carriers of Plasmodium falciparum Infections

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.05359-11 ◽

2012 ◽

Vol 56 (6) ◽

pp. 3165-3173 ◽

Cited By ~ 57

Author(s):

Christian Supan ◽

Ghyslain Mombo-Ngoma ◽

Matthias P. Dal-Bianco ◽

Carmen L. Ospina Salazar ◽

Saadou Issifou ◽

...

Keyword(s):

Plasmodium Falciparum ◽

Oral Dose ◽

Dose Range ◽

Young Male ◽

Double Blind ◽

Time Curve ◽

Blood Concentrations ◽

Content Type ◽

Dose Linearity ◽

Dose Study

ABSTRACTFerroquine (SSR97193), a ferrocene-quinoline conjugate, is a promising novel antimalarial currently undergoing clinical evaluation. This study characterizes its pharmacokinetic properties. Young male African volunteers with asymptomaticPlasmodium falciparuminfection were administered a single oral dose (n= 40) or a repeated oral dose (n= 26) given over 3 days of ferroquine in two dose-escalation, double-blind, randomized, placebo-controlled clinical trials. In addition, a food interaction study was performed in a subsample of participants (n= 16). The studies were carried out in Lambaréné, Gabon. After single-dose administration of ferroquine, dose linearity was demonstrated in a dose range of 400 to 1,200 mg for maximum mean blood concentrations ([Cmax] 82 to 270 ng/ml) and in a dose range of 400 to 1,600 mg for overall exposure to ferroquine (area under the concentration-time curve [AUC], 13,100 to 49,200 ng · h/ml). Overall mean estimate for blood apparent terminal half-life of ferroquine was 16 days and 31 days for its active and major metabolite desmethylferroquine (SSR97213). In the 3-day repeated-dose study,Cmaxand overall cumulated exposure to ferroquine (AUCcum) increased in proportion with the dose from day 1 to day 3 between 400 and 800 mg. No major food effect on ferroquine pharmacokinetics was observed after single administration of 100 mg of ferroquine except for a slight delay of time to maximum blood concentration (tmax) by approximately 3 h. The pharmacokinetics of ferroquine and its active main metabolite are characterized by sustained levels in blood, and the properties of ferroquine as a partner drug in antimalarial combination therapy should be evaluated.

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GBT440 Demonstrates High Specificity for Red Blood Cells in Nonclinical Species

Blood ◽

10.1182/blood.v126.23.2172.2172 ◽

2015 ◽

Vol 126 (23) ◽

pp. 2172-2172 ◽

Cited By ~ 3

Author(s):

Athiwat Hutchaleelaha ◽

Mira Patel ◽

Abel Silva ◽

Donna Oksenberg ◽

Brian Metcalf

Keyword(s):

Oral Dose ◽

Oral Administration ◽

Sickle Cell ◽

Blood Cells ◽

Ex Vivo ◽

The Body ◽

Cell Disease ◽

Employment Equity ◽

Blood Concentrations ◽

Equity Ownership

Abstract Sickle cell disease (SCD) is caused by a point mutation in the β-globin gene leading to production of hemoglobin S (HbS) that polymerizes upon deoxygenation with subsequent formation of sickled red blood cells (RBCs). GBT440 modulates O2 affinity of hemoglobin (Hb) by binding to the N-terminal α chain of Hb via a reversible Schiff base. We previously demonstrated that GBT440 preventedsickling of RBCs from sickle cell patients, in vitro. Also, in a murine model of sickle cell disease (Townes SS mice), GBT440 prevented ex vivo sickling of RBCs and prolonged RBC half-life. Pharmacokinetic (PK) studies of GBT440 were conducted in mouse, rat, dog and monkey following IV and oral administration. Both blood and plasma samples were collected and assayed for GBT440 concentration using LCMS. Following IV and oral administrations, GBT440 quickly partitions into the RBC with a high blood/plasma ratio of ~70:1 which corresponded to a RBC/plasma ratio of ~150:1. Volume of distribution (Vss) was small in whole blood (0.041-0.171 L/kg) but much larger in plasma (1.44-8.45 L/kg) indicating that RBCs are a reservoir of GBT440. Systemic clearance (CLs) was low in both blood (0.016-0.113 mL/min/kg) and plasma (0.943-3.16 mL/min/kg) indicating that GBT440 was mostly bound to hemoglobin and only a small fraction of unbound GBT440 re-distributed into the plasma and was available for clearance. Terminal elimination half-life (t1/2) was similar between whole blood and plasma for each species and was long, ranging from 6.4 hours in mouse plasma to 93.5 hours in dog plasma. GBT440 was well absorbed and absolute oral bioavailability ranged from 33% to 70% in four species. A quantitative whole body autoradiography study to determine tissue distribution of GBT440 was conducted in male rats following an oral dose of 14C-GBT440 (10 mg/kg; 150 µCi/kg PO). The data showed that GBT440 is co-located in hematopoietic tissues as expected for a molecule whose target is hemoglobin, including blood, spleen, liver and bone marrow. A mass balance study of 14C-GBT440 (10 mg/kg; 150 µCi/kg PO) was conducted in rats to determine route of elimination of GBT440. The 14C-GBT440-derived radioactivity was well absorbed and rapidly excreted after oral administration. By 240 hours postdose, mean values of 79.0 ± 3.86 and 9.74 ± 3.02% of the administered radioactivity were excreted in feces and urine, respectively. The mean overall recovery of radioactivity was 92.4 ± 0.875%. Metabolism via both Phase I and Phase II pathways was the major route of elimination of GBT440. These data indicate that despite its high affinity binding toward Hb, GBT440 could be released from the hemoglobin complex and completely eliminated from the body. To further correlate PK to pharmacological activity (hemoglobin modification based on changes in the oxygen equilibrium curve), mice were given an oral dose of 30, 50 and 100 mg/kg and blood were collected at 4 and 6 hr postdose for hemoximetry analysis. Data showed good correlation between blood concentrations and changes in p50. Blood concentrations following 30, 50 and 100 mg/kg at 4 hr were 243, 446, and 806 µM, which resulted in changes in p50 of 11%, 25% and 55%, respectively, indicating that GBT440 elicits an ex vivo dose dependent increase in Hb-O2 affinity following increasing dosage to mice. Based on PK data from 4 animal species, PK profile of GBT440 in human was predicted using a simple allometric scaling technique. The predicted PK profile following an oral administration was highly concordant with actual data from healthy subjects for Cmax, AUC and T½, which suggested that the disposition kinetics of GBT440 in humans were consistent to that in animals. In summary, nonclinical PK studies support previous findings that GBT440 partitions to RBCs, binds specifically to Hb with a slow off rate, modulates Hb-O2 affinity, and is completely eliminated from the body. GBT440 is in clinical trials for the treatment of SCD. Disclosures Hutchaleelaha: Global Blood Therapeutics: Employment, Equity Ownership. Patel:Global Blood Therapeutics: Employment, Equity Ownership. Silva:Global Blood Therapeutics: Employment, Equity Ownership. Oksenberg:Global Blood Therapeutics: Employment, Equity Ownership. Metcalf:Global Blood Therapeutics: Consultancy, Equity Ownership.

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Suppression of Non-Esterified Fatty Acids and Triacylglycerol in Experimental Animals by the Adenosine Analogue GR79236

Clinical Science ◽

10.1042/cs0840663 ◽

1993 ◽

Vol 84 (6) ◽

pp. 663-669 ◽

Cited By ~ 28

Author(s):

P. Strong ◽

R. Anderson ◽

J. Coates ◽

F. Elus ◽

B. Evans ◽

...

Keyword(s):

Fatty Acids ◽

Oral Administration ◽

Dose Range ◽

Blood Concentrations ◽

Esterified Fatty Acids ◽

Pithed Rats ◽

A1 Receptor ◽

Isolated Adipocytes ◽

Dose Dependent

1. This is the first description of the metabolic activity of a novel adenosine A1-receptor agonist, GR79236. GR79236 inhibited catecholamine-induced lipolysis in human, rat and dog isolated adipocytes. 2. Oral administration of GR79236 (0.1-10 mg/kg) to fed rats induced minimal changes in the plasma concentration of non-esterified fatty acids and in the blood concentrations of glucose and lactate. 3. Intravenous infusion of GR79236 to fasted pithed rats, or oral administration of GR79236 to fasted conscious rats and dogs, produced time- and dose-dependent decreases in the plasma non-esterified fatty acid concentration. In the fasted rats, doses of GR79236 that lowered plasma levels of non-esterified fatty acids also produced hypotriglyceridaemia and anti-ketotic effects. 4. Only in the pithed rats were acute effects on the plasma glucose and lactate concentrations observed. Hypoglycaemia and hyperlactataemia occurred over the dose range studied (1 × 10−11-1 × 10−8 mol min−1 kg−1). 5. This profile of activity suggests that compounds such as GR79236 might be agents which can be used to define the role of excessive lipolysis in experimental (and human) pathophysiology.

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Characterising the plasma-target occupancy relationship of the neurokinin antagonist GSK1144814 with PET

Journal of Psychopharmacology ◽

10.1177/0269881113517953 ◽

2014 ◽

Vol 28 (3) ◽

pp. 244-253 ◽

Cited By ~ 10

Author(s):

Khanum Ridler ◽

Roger N Gunn ◽

Graham E Searle ◽

Julien Barletta ◽

Jan Passchier ◽

...

Keyword(s):

Single Dose ◽

Plasma Concentration ◽

Human Brain ◽

Dose Range ◽

Receptor Occupancy ◽

Repeat Dose ◽

Dose Selection ◽

Dose Administration ◽

Single Dose Administration

GSK1144814 is a potent, insurmountable antagonist at human NK1 and NK3 receptors. Understanding the relationship between plasma pharmacokinetics and receptor occupancy in the human brain, was crucial for dose selection in future clinical studies. GSK1144814 occupancy data were acquired in parallel with the first-time-in-human safety and tolerability study. [11C]GR-205171 a selective NK1 receptor PET ligand was used to estimate NK1 occupancy at several time-points following single dose administration of GSK1144814. The time-plasma concentration–occupancy relationship post-single dose administration was assessed, and used to predict the plasma concentration–occupancy relationship following repeat dose administration. Repeat dose predictions were tested in a subsequent cohort of subjects examined following approximately 7 and 14 days dosing with GSK1144814. GSK1144814 was shown to demonstrate a dose-dependent occupancy of the NK1 receptor with an estimated in vivo EC50 ~0.9 ng/mL in the human brain. A direct relationship was seen between the GSK1144814 plasma concentration and its occupancy of the brain NK1 receptor, indicating that in future clinical trials the occupancy of brain receptors can be accurately inferred from the measured plasma concentration. Our data provided support for the further progression of this compound and have optimised the likely therapeutic dose range.

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Abstract 12650: A Faster and Safe Way for Dose Escalation of Sotalol Therapy in Patients With Atrial Fibrillation or Flutter

Circulation ◽

10.1161/circ.142.suppl_3.12650 ◽

2020 ◽

Vol 142 (Suppl_3) ◽

Author(s):

John C Somberg ◽

Alexander A Vinks ◽

Min Dong ◽

janos molnar

Keyword(s):

Atrial Fibrillation ◽

Oral Dose ◽

Oral Administration ◽

Dose Escalation ◽

Torsade De Pointes ◽

Estimation Method ◽

Bioequivalence Study ◽

Population Pharmacokinetic ◽

Blood Concentrations ◽

Population Pharmacokinetic Modeling

Sotalol is frequently employed to prevent the recurrence of highly symptomatic atrial fibrillation or flutter, but recurrence is not unusual and may require dose escalation. Sotalol can cause QTc prolongation proportional to blood concentration and at times may cause Torsade de Pointes ventricular tachycardia (TdP). Because the risk of TdP, dose escalation of oral sotalol therapy is mandated by FDA to be in-hospital for a minimum of 3 days under ECG monitoring with facilities and personnel able to provide cardiac resuscitation. With oral administration (bid), 3 days are needed to reach the new maximal steady-state blood concentrations (Cmax ss) and thus maximal QTc . Three hospital days in a telemetry bed is costly of time and resources. IV sotalol makes it possible to reduce the escalation time from 3 days to 1 day. The IV to oral dose escalation has been developed by model informed drug development. Serum sotalol concentrations and corresponding QTc were obtained from a bioequivalence study in healthy volunteers who received a single dose of oral and IV sotalol. NONMEM software package was used for population pharmacokinetic modeling and simulation. First Order Conditional Estimation method with Interaction (FOCE-INTER) was used for computation. We chose to administer IV sotalol over 1 hour to obtain the new Cmax ss target in a timeframe convenient for medical staff to supervise. Simulation for dose escalation from 80 to 120 mg bid is shown in the Figure; 75 mg IV sotalol is administered over 1 hour followed by 120 mg oral sotalol at 5 hours from start of infusion, then a second oral dose of 120 mg at 12 hours. One can target escalation from 120 to 160 mg by loading 90 mg IV over 1 hr followed by 160 mg oral dosing. Sotalol concentration will peak in 2-4 hours following each oral administration, thus in 21 hour there will be 3 sotalol peak concentrations. This permits evaluation of QTc response and risk of TdP all within a 1 day admission.

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Bioequivalence Study of Two Formulations of Febuxostat 120 mg Film-coated Tablets in Healthy Adult Volunteers After a Single Oral Dose Administration Under Fasting Conditions

Case Medical Research ◽

10.31525/ct1-nct03918551 ◽

2019 ◽

Author(s):

Keyword(s):

Oral Dose ◽

Single Oral Dose ◽

Healthy Adult ◽

Bioequivalence Study ◽

Dose Administration ◽

Adult Volunteers

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The Bioequivalence Study of Two Different Formulations of Candesartan Cilexetil After a Single Oral Dose Administration Under Fasting Conditions

Case Medical Research ◽

10.31525/ct1-nct04012307 ◽

2019 ◽

Author(s):

Keyword(s):

Oral Dose ◽

Single Oral Dose ◽

Candesartan Cilexetil ◽

Bioequivalence Study ◽

Dose Administration

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Blood concentrations of dihydroxylated vitamin D metabolites after an oral dose.

BMJ ◽

10.1136/bmj.280.6212.449-a ◽

1980 ◽

Vol 280 (6212) ◽

pp. 449-450 ◽

Cited By ~ 28

Author(s):

R S Mason ◽

D Lissner ◽

S Posen ◽

A W Norman

Keyword(s):

Vitamin D ◽

Oral Dose ◽

Vitamin D Metabolites ◽

Blood Concentrations

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Phase I Dose-Finding Study of Weekly Single-Agent Patupilone in Patients With Advanced Solid Tumors

Journal of Clinical Oncology ◽

10.1200/jco.2005.03.0981 ◽

2005 ◽

Vol 23 (36) ◽

pp. 9120-9129 ◽

Cited By ~ 84

Author(s):

Eric H. Rubin ◽

John Rothermel ◽

Fisseha Tesfaye ◽

Tianling Chen ◽

Martine Hubert ◽

...

Keyword(s):

Partial Response ◽

Solid Tumors ◽

Half Life ◽

Drug Exposure ◽

Dose Range ◽

Single Agent ◽

Dose Finding ◽

Advanced Solid Tumors ◽

Blood Concentrations ◽

Terminal Half Life

Purpose To evaluate the safety and maximum-tolerated dose (MTD) of weekly patupilone, a natural epothilone B, in patients with advanced solid tumors. Patients and Methods Patients were treated with patupilone (0.3 to 3.6 mg/m2) for 6 weeks on/3 weeks off or 3 weeks on/1 week off. Dose-limiting toxicities (DLTs), MTD, and pharmacokinetics were determined for each schedule of administration. Results Ninety-one patients were enrolled. The most common tumor types included ovarian, breast, and colon cancers. Doses of patupilone less than 2.5 mg/m2 using either the 6 weeks on/3 weeks off or the 3 weeks on/1 week off schedule were tolerated well. At higher doses, DLTs were observed using both dosing schedules, with diarrhea the most common DLT. The MTD for both treatment schedules was 2.5 mg/m2. After a short infusion, patupilone blood concentrations declined in a multiphasic manner with a terminal half-life of 4 days. Drug clearance was nonrenal and was not related to body-surface area. Over the dose range evaluated, systemic drug exposure was approximately dose proportional. Three patients achieved a partial response, and 31 patients had stable disease. Two patients experiencing a partial response had received prior taxane therapy. Conclusion Patupilone is well tolerated when administered at a dose of 2.5 mg/m2, using either a 6 weeks on/3 weeks off or a 3 weeks on/1 week off schedule. In contrast with murine studies, patupilone has a relatively prolonged terminal half-life in humans. The partial responses in patients previously treated with taxanes is consistent with promising preclinical results.

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