Single Oral Doses of a Novel Thrombopoietin Mimetic ONO-7746 Increase Platelet Counts In Healthy Subjects

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4827-4827
Author(s):  
Thomas L Hunt ◽  
Ming Q. Lu ◽  
Yasushi Kawasaki ◽  
John P. Hall ◽  
Junji Komaba ◽  
...  
Keyword(s):  
Adverse Event ◽  
Platelet Count ◽  
Single Dose ◽  
Dose Escalation ◽  
Healthy Subjects ◽  
Dose Range ◽  
Plasma Concentrations ◽  
Stopping Rules ◽  
Platelet Counts ◽  
The Mean

Abstract Abstract 4827 Objective: A novel orally administered small-molecule thrombopoietin receptor (c-Mpl) agonist, ONO-7746, was investigated in a double-blind, placebo-controlled single dose escalation study for its safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) in healthy subjects. Methods: A total of 48 subjects were enrolled into 6 cohorts of 8 subjects each. For each cohort, subjects were randomly assigned to receive ONO-7746 or placebo in a 3:1 ratio. After a single dose of study drug on Day 1 of each cohort, all subjects in a cohort were assessed on Day 21 for their overall safety, tolerability and changes in platelet count prior to proceeding to the next higher dose. The doses of ONO-7746 applied for each successive cohort were adjusted per Dose-Escalation and Stopping Rules, i.e. the successive dose was only a 1.5-fold increase from the previous dose if either of the following were observed: Two subjects had a platelet count increase greater than 400 × 109/L, or had a platelet count doubling from Baseline. Further dose escalation was terminated if 50% of the subjects in a cohort (4 subjects) demonstrated a platelet count increase > 400 × 109/L or doubling from Baseline. This study completed a total of 6 cohorts including 5, 10, 20, 50, 100, and 150 mg. Intensive safety, tolerability, PK, and PD assessments were made throughout the study. Safety assessments included 12-lead ECGs, vital signs, serum chemistry, hematology, urinalysis and adverse event (AE) reporting. Plasma samples for ONO-7746 concentration-time analysis were collected at several time points. PD parameters included platelet count, platelet activation, and aggregation. Results: Dose escalation was only increased 1.5-fold after the 100-mg cohort because of increases in platelet count, and dose escalation was ultimately terminated after the 150-mg cohort because 50% of subjects had a platelet count increase to > 400 × 109/L or doubling from Baseline. The mean platelet counts in the ONO-7746 cohorts increased from Baseline beginning on Days 3 or 4, peaked between Days 9 and 11, decreased from Days 11 or 13, and returned to baseline levels by Day 28. Maximum platelet count, change from Baseline values increased with ascending ONO-7746 dose level. The largest percent change from Baseline in platelet count (117.0%) was observed in the 150-mg cohort, compared with 14.7% in the placebo cohort. Platelet function as measured by the exploratory platelet aggregation and activation tests was not affected by administration of ONO-7746. The PK profile of ONO-7746 showed that the plasma concentrations reached Cmax at a median Tmax of 3.0 to 4.0 hours. The mean T1/2 ranged from 22 to 27 hours. The PK of ONO-7746 was linear in the dose range of 5 to 100 mg. In the dose range of 100 to 150 mg, Cmax and AUCinf increased greater than dose proportionally. One subject in the 150-mg cohort had an adverse event of special interest (AESI) of increased platelet count > 500 × 109/L that was considered mild in severity. There were no deaths, serious AEs, severe AEs, or AEs that led to study discontinuation. No treatment- or dose-related trends were observed in AEs, clinical laboratory results, vital sign measurements, 12-lead ECG and telemetry results. Conclusion: The above observations indicate that ONO-7746 could increase platelet count even with a single dose. ONO-7746 is a potent once-daily oral c-Mpl agonist with demonstrated thrombopoietic activity in human subjects, safe and well tolerated at all the tested dose levels (5, 10, 20, 50, 100 and 150 mg). Observed Platelet Count by Study Day Disclosures: Hunt: ONO Pharma USA: Research Funding. Lu:ONO Pharma USA: Employment. Kawasaki:Ono Pharmaceutical Co., Ltd.: Employment. Hall:ONO Pharma USA: Employment. Komaba:ONO Pharma USA: Employment. Takeuchi:Ono Pharmaceutical Co., Ltd.: Employment. Imamura:ONO Pharma USA: Employment. Kuter:ONO Pharma USA: Consultancy.

A Double-Blind, Placebo-Controlled, and Multiple Dose Escalation Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Ono-7746 in Healthy Subjects

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4828-4828
Author(s):  
Thomas L Hunt ◽  
Ming Q. Lu ◽  
Yasushi Kawasaki ◽  
John P. Hall ◽  
Junji Komaba ◽  
...  
Keyword(s):  
Adverse Event ◽  
Platelet Count ◽  
Single Dose ◽  
Dose Escalation ◽  
Healthy Subjects ◽  
Multiple Dose ◽  
Dose Administration ◽  
Once Daily ◽  
Cell Counts ◽  
Multiple Dose Administration

Abstract Abstract 4828 Background: ONO-7746 is a potent orally administered thrombopoietin receptor (c-Mpl) agonist and can elevate platelet counts after a single dose in healthy subjects. Therefore, it could be potentially used for the treatment of thrombocytopenia associated with a variety of etiologies. Objectives: This study evaluated the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of ONO-7746 after multiple dose administration in healthy subjects. Methods: A total of 60 subjects were randomly assigned to 5 groups of 12 subjects each to receive active ONO-7746 (9 subjects) or placebo (3 subjects) once daily for 14 days at doses of 1, 2, 4, 6, and 10 mg per day. Dose selection was adjusted based on data from earlier cohorts according to the dose-escalation procedures, i.e. Dose escalation was only permitted if adequate safety and tolerability were demonstrated and the results did not meet the stopping rule criteria at the previous dose level as described in the single-dose study. Subjects returned on Day 42 for follow-up assessments. ONO-7746 was administered once daily under fasted conditions at the dose of 1 mg to 10 mg for 14 days. Subjects were admitted to the clinical study site on Day –1 and remained at the site until discharge on Day 32. Intensive safety, tolerability, PK, and PD assessments were made throughout the study. Safety assessments included 12-lead ECGs, vital signs, serum chemistry, hematology, urinalysis and adverse event (AE) reporting. Plasma samples for ONO-7746 concentration-time analysis were collected at several time points. PD parameters included platelet count, platelet activation, and aggregation. Results: Maximum platelet count and change from Baseline values increased with ascending ONO-7746 dose level. The mean platelet counts in the ONO-7746 cohorts increased from Baseline beginning on Days 3 or 4, peaked between Days 12 and 17, decreased from Days 22 to 32, and returned to baseline levels by Day 42. The largest mean percent change from Baseline in average platelet count (145.9%) was observed in the 10-mg cohort, compared with 17.4% in the placebo cohort. Platelet function as measured by the exploratory platelet aggregation and activation tests was not affected by administration of ONO-7746. In general, endogenous TPO values and CD34+ cell counts seemed not to be affected by the administration of ONO-7746. The PK profiles of ONO-7746 showed that Cmax and AUC24h increased with dose and T1/2 after the last dose was similar to that after a single dose. The plasma trough concentration of ONO-7746 reached steady state by Day 10. The PK of ONO-7746 was not affected by multiple-dose administration. Six subjects in the 10-mg cohort had an adverse event of special interest (AESI) of increased platelet count > 500 × 109/L. No treatment- or dose-related trends were observed in AEs, clinical laboratory results, influence on other blood cell counts, physical examination findings, vital sign measurements, 12-lead ECG and telemetry results, or slit lamp examination results. There were no deaths, serious AEs, severe AEs, or AEs that led to study discontinuation. Conclusion: ONO-7746 is safe and well-tolerated at all tested dose levels. The PK, PD, and safety profile demonstrated in this study supports further clinical studies in thrombocytopenic patients. Observed Platelet Count by Study Day Disclosures: Hunt: ONO Pharma USA: Research Funding. Lu:ONO Pharma USA: Employment. Kawasaki:Ono Pharmaceutical Co., Ltd.: Employment. Hall:ONO Pharma USA: Employment. Komaba:Ono Pharmaceutical Co., Ltd.: Employment. Takeuchi:Ono Pharmaceutical Co., Ltd.: Employment. Imamura:ONO Pharma USA: Employment. Kuter:ONO Pharma USA: Consultancy.

A Phase 2 Open-Label, Sequential-Cohort, Dose-Escalation Study of AMG 531 in Japanese Patients with Chronic Immune Thrombocytopenic Purpura (ITP).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1308-1308
Author(s):  
Yukari Shirasugi ◽  
Kiyoshi Ando ◽  
Satoshi Hashino ◽  
Toshiro Nagasawa ◽  
Yoshiyuki Kurata ◽  
...  
Keyword(s):  
Platelet Count ◽  
Dose Escalation ◽  
Japanese Patients ◽  
Phase 2 ◽  
Platelet Response ◽  
Phase 3 ◽  
Continuation Phase ◽  
Platelet Counts ◽  
Starting Dose ◽  
The Mean

Abstract AMG 531 is a novel thrombopoiesis-stimulating peptibody that is being studied for its ability to increase platelet production by stimulating the thrombopoietin (TPO) receptor. This phase 2 study was conducted to identify the appropriate starting dose of AMG 531 for treatment of chronic ITP in adult Japanese patients. The study consisted of 2 phases: a 2-week cohort dose-escalation phase to determine the starting dose for subsequent phase 3 evaluation, and a treatment continuation phase (that lasted until completion of the dose-escalation phase) which provided continuation of treatment for those with a platelet response. Patients in the continuation phase received the dose of AMG 531 they had received in the dose-escalation phase with the option for subsequent dose adjustments. Twelve patients were enrolled with a mean platelet count of 11.8x109/L and a median age of 60.5 years (range 32 to 63); 8 were female. Four patients enrolled into each of 1μg/kg, 3μg/kg, or 6μg/kg dose cohorts and received AMG 531 by subcutaneous injection on days 1 and 8 with no dose adjustments. Cohort dose escalation was to be stopped in the event of an observed platelet count >1000x109/L. Comparison of dose cohorts showed that the proportion of patients achieving a platelet response (doubling of baseline counts and ≥50x109/L) was greater in cohorts receiving higher doses of AMG 531 (see Table). A dose response was also observed in the mean peak platelet counts, the mean fold changes from baseline in peak platelet counts, and the maximum platelet count. Because one patient in the 6μg/kg cohort had an excessively high platelet count (980x109/L), this dose was eliminated from consideration as the starting dose in phase 3 and further dose escalation to 10μg/kg dose cohort was stopped. Five of 7 eligible patients (3μg/kg, 1/4; 6μg/kg, 4/4) elected to enter the treatment continuation phase. There were no study withdrawals, and no serious adverse events (AEs) were reported during the study in either phase. The most common treatment-related AE in the cohort phase was headache (25%), and in the treatment continuation phase were arthralgia, contact dermatitis, and malaise (each 20%). No patients received rescue medications during the entire treatment period. No antibodies against either AMG 531 or endogenous TPO were detected. AMG 531 was well-tolerated and produced a dose-responsive increase in platelet counts. The phase 3 study in Japanese patients with ITP will be initiated with a starting dose of 3μg/kg based on the outcome of this study. Key Measures of Platelet Response

scholarly journals Open-Label, Dose Escalation Study of the Safety and Pharmacokinetic Profile of Tefibazumab in Healthy Volunteers

2005 ◽  
Vol 49 (3) ◽  
pp. 959-962 ◽  
Author(s):  
Sandra Reilley ◽  
Eric Wenzel ◽  
Laurie Reynolds ◽  
Beth Bennett ◽  
Joseph M. Patti ◽  
...  
Keyword(s):  
Healthy Volunteers ◽  
Dose Escalation ◽  
Maximum Concentration ◽  
Dose Range ◽  
Plasma Concentrations ◽  
Open Label ◽  
Serious Adverse Events ◽  
Dose Escalation Study ◽  
Label Dose ◽  
The Mean

ABSTRACT Tefibazumab (Aurexis) is a humanized monoclonal antibody being evaluated as adjunctive therapy for the treatment of Staphylococcus aureus infections. This open-label, dose escalation study evaluated the safety and pharmacokinetics of tefibazumab in 19 healthy volunteers aged 18 to 69 years. Each subject received a single administration of tefibazumab at a dose of 2, 5, 10, or 20 mg/kg of body weight infused over 15 min. Plasma samples for pharmacokinetic assessments were obtained before infusion as well as 1, 6, 12, and 24 h and 3, 4, 7, 21, 28, 42, and 56 days after dosing. Plasma concentrations of tefibazumab were detected 1 h after the end of the infusion, with a mean maximum concentration of drug in serum (C max) of 59, 127, 252, and 492 μg/ml following doses of 2, 5, 10, and 20 mg/kg, respectively. The median time to maximum concentration of drug in serum (T max) was 1.0 h for each dose. The mean elimination half-life (t 1/2) was approximately 22 days. The volume of distribution (V) was 4.7, 6.7, 7.2, and 7.2 liters after doses of 2, 5, 10, and 20 mg/kg, respectively. Clearance (CL) was 6.0, 9.2, 10.2, and 9.9 ml/hr, respectively. At the highest dose, plasma levels of tefibazumab were >100 μg/ml for 21 days. On day 56, the mean plasma concentrations were 6.3, 10.0, 16.4, and 30.5 μg/ml for the 2, 5, 10, and 20 mg/kg doses, respectively. Tefibazumab exhibited linear kinetics across doses of 5, 10, and 20 mg/kg. No anti-tefibazumab antibodies were detected after dosing in any subject. There were no serious adverse events, and tefibazumab was well tolerated over the entire dose range.

Effects of biological variations on platelet count in healthy subjects in China

2004 ◽  
Vol 91 (02) ◽  
pp. 367-372 ◽  
Author(s):  
Jing Yang ◽  
Xiaojun Lu ◽  
Tokuhiro Okada ◽  
Tamiaki Kondo ◽  
Changgeng Ruan ◽  
...  
Keyword(s):  
Platelet Count ◽  
Mean Platelet Volume ◽  
Healthy Subjects ◽  
Bleeding Time ◽  
Platelet Volume ◽  
Platelet Counts ◽  
Normal Platelet Count ◽  
Normal Platelet ◽  
Low Platelet Count ◽  
The Mean

SummaryThe effects of biological variations on platelet counts were investigated in 694 healthy subjects aged 18 to 60 years living in three cities including Chengdu (Sichuan Province), Suzhou (Jiangsu Province) and Harbin (Heilongjang Province) in China. Platelet counts in healthy subjects were significantly lower in Chengdu (52∼202 X 109/L) and Suzhou (60∼259 X 109/L) than in Harbin (154∼348 X 109/L)(p <0.0001), but the mean platelet volume (MPV) determined concurrently was negatively correlated with platelet count, the MPV values were significantly higher in Chengdu (11.8∼15.6 fl) and Suzhou (10.9∼15.8 fl) than in Harbin (9.5∼12.9 fl) (p < 0.0001). Platelet counts were significantly higher in summer (73∼289 X 109/L) than in winter (52∼202 X 109/L) (p <0.0001), but the MPV values were lower in summer (11.2∼14.7 fl) than in winter (11.8∼15.6 fl) (p <0.05) in Chengdu. Platelet associated immunoglobulin (PA-IgG) in Chengdu was revealed to be significantly higher in the low platelet count group (<150 X 109/L, 13.5 ± 7.1 ng/107 PLT) than in the normal platelet count group (≥150 X 109/L, 8.3 ± 2.7 ng/107 PLT)(p <0.0001). Similar results were observed in Suzhou for the reticulated platelet ratio, which was significantly higher in the low platelet count group (19.5 ± 7.1%) than in the normal platelet count group (11.6 ± 2.7%)(p <0.01). The bleeding time in Chengdu showed a significantly longer time in the low platelet count group (8.6 ± 2.3 min) than in the normal platelet count group (6.0 ± 1.2 min)(p <0.01). With regard to the effects of lipids on platelet counts, the HDL values were significantly higher in the normal platelet count group (1.60 ± 0.76 mmol/L) than the low platelet count group (1.23 ± 0.31 mmol/L) (p <0.01); but no significant differences in cholesterol and triglycerides values between the normal and low platelet count groups (p >0.05) were recorded. These findings suggest that the platelet counts could be greatly influenced in healthy subjects by biological variations such as geographical, seasonal, and lipid variations.

Ibuprofen: Plasma Concentrations in Man

1985 ◽  
Vol 13 (1) ◽  
pp. 68-73 ◽  
Author(s):  
G M E Janssen ◽  
J F Venema
Keyword(s):  
Side Effects ◽  
Crossover Study ◽  
Plasma Levels ◽  
Healthy Subjects ◽  
Peak Plasma ◽  
Plasma Concentrations ◽  
Repeated Dose ◽  
Similar Range ◽  
The Mean ◽  
Peak Value

The plasma levels of Ibuprofen were measured in five healthy subjects who took 600 mg tablets of Ibuprofen twice daily, three times daily and four times daily in a crossover study. Peak plasma levels were obtained 1 hour after the first dose in all but one subject (slow absorber), the mean peak value being 51·3 μg.ml−1 (range 39·4–63·7 μg.ml−1). After the repeated dose regimens of two, three or four times daily of ibuprofen, the peak levels achieved were in a similar range to those seen after the first dose: Twice daily 39·4–66·4 μg.ml−1 Three times daily 43·6–63·3 μg.ml−1 Four times daily 44·1–58·4 μg.ml−1 There was no evidence of accumulation of the drug and no side-effects occurred during the trial.

Studies on Reference Intervals for Platelet Counts in Three Cities in China and one in Japan

2002 ◽  
Vol 88 (07) ◽  
pp. 111-114 ◽  
Author(s):  
Changgeng Ruan ◽  
Yun Wu ◽  
Tokuhiro Okada ◽  
Shigemi Motoi ◽  
Tamiaki Kondo ◽  
...  
Keyword(s):  
Platelet Count ◽  
Mean Platelet Volume ◽  
Healthy Subjects ◽  
Hematological Parameters ◽  
Reference Interval ◽  
Reference Intervals ◽  
Sichuan Province ◽  
Jiangsu Province ◽  
Platelet Volume ◽  
Platelet Counts

SummaryHematological parameters including platelet counts, etc. were determined in 1,140 healthy subjects living in four cities: Suzhou (Jiangsu Province), Chengdu (Sichuan Province) and Harbin (Heilongjang Province) in China, and Kobe in Japan. Then, the reference intervals for platelet counts were calculated and compared. The reference interval for platelet count of subjects aged between 18 and 60 years was 60-259 × 109/L in Suzhou and 52–202 × 109/L in Chengdu, and subjects with platelet counts of 100 × 109/L or less accounted for about 30% of the subjects examined in these cities. The reference intervals in Harbin and Kobe were within the range of 150–350 × 109/L, and no subject having a platelets count of 100 × 109/L or less was detected. Mean platelet volume (MPV) determined concurrently was negatively correlated with platelet count, and the reference intervals for MPV in Chengdu and Suzhou were higher than those in Harbin and Kobe.

scholarly journals Opposite Effects of Single-Dose and Multidose Administration of the Ethanol Extract of Danshen on CYP3A in Healthy Volunteers

2013 ◽  
Vol 2013 ◽  
pp. 1-8 ◽  
Author(s):  
Furong Qiu ◽  
Jian Jiang ◽  
Yueming Ma ◽  
Guangji Wang ◽  
Chenglu Gao ◽  
...  
Keyword(s):  
Single Dose ◽  
Healthy Volunteers ◽  
Plasma Concentrations ◽  
In Vitro Study ◽  
Ethanol Extract ◽  
Tanshinone Iia ◽  
Open Label ◽  
The Mean

The aim of this study was to investigate the effect of single- and multidose administration of the ethanol extract of danshen on in vivo CYP3A activity in healthy volunteers. A sequential, open-label, and three-period pharmacokinetic interaction study design was used based on 12 healthy male individuals. The plasma concentrations of midazolam and its metabolite 1-hydroxymidazolam were measured. Treatment with single dose of the extract caused the meanCmaxof midazolam to increase by 87% compared with control. After 10 days of the danshen extract intake, the mean AUC0–12,Cmax, andt1/2of midazolam were decreased by 79.9%, 66.6%, and 43.8%, respectively. The mean clearance of midazolam was increased by 501.6% compared with control. The in vitro study showed that dihydrotanshinone I in the extract could inhibit CYP3A, while tanshinone IIA and cryptotanshinone could induce CYP3A. In conclusion, a single-dose administration of the danshen extract can inhibit intestinal CYP3A, but multidose administration can induce intestinal and hepatic CYP3A.

Multiple Cycles of Recombinant Human Thrombopoietin Therapy in a Patient with Chronic Refractory Idiopathic Thrombocytopenic Purpura.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3933-3933
Author(s):  
Yongqiang Zhao ◽  
Baolai Hua ◽  
Nong Zou ◽  
Shujie Wang ◽  
Tienan Zhu
Keyword(s):  
Platelet Count ◽  
Idiopathic Thrombocytopenic Purpura ◽  
Immunosuppressive Agents ◽  
Plasma Concentrations ◽  
Thrombocytopenic Purpura ◽  
Platelet Production ◽  
Platelet Counts ◽  
Multiple Cycles ◽  
Recombinant Human Thrombopoietin ◽  
Refractory Itp

Abstract Thrombopoietin (TPO) is the key regulator of megakaryocytepoiesis and platelet production. TPO binds to its specific receptor, c-Mpl, on the surfaces of megakaryocytes, and may promote the proliferation, differentiation and maturation of megakaryocytes, and finally increase the circulating platelet count. The role of TPO in the pathogenesis of idiopathic thrombocytopenic purpura (ITP) is not certain. Plasma concentrations of TPO in ITP patients were similar to or little lower than that in healthy subjects. Therefore it is possible that supplemental TPO could significantly promote platelet production and increase platelet counts in ITP patients. Here, we report the result of multiple cycles of recombinant human thrombopoietin (rhTPO) therapy in a patient with refractory ITP. The patient, a 42-year-old woman, was admitted to our department on December 30, 2003. She had suffered from chronic ITP for more than 4 years. The patient had been treated with glucocorticosteroids, immunosuppressive agents and splenectomy. No sustained response could be achieved. The diagnosis of chronic refractory ITP was made. There were petechiae and gingival bleeding on admission. Liver and spleen were not palpable. Hemoglobin was 142g/L, white blood cell count 7.6×10 9/L, platelet count 15×10 9/L. Bone marrow aspiration revealed that erythroid and myeloid development were normal, megakaryocytes were increased in number and no dysplastic features. After an informed consent was obtained from the patient, rhTPO (Sunshine Pharmaceutical Corporation, China) was administrated subcutaneously at dosage of 1.0 μg/kg, daily for 14 days or until platelet count sustained more than 50×109/L. Anti-rhTPO antibodies were determined weekly by ELISA. Three cycles of rhTPO therapy was given with 6, 13 and 8 dosing for each cycle. The platelet counts before each cycle were all less than10×109/L and increased above 50×109/L on day 5, 11 and 8 of rhTPO administration, respectively. The peak platelet counts of 456, 130 and 82×109/L were reached on day 9, 15 and 13 for each cycle. Then platelet count decreased gradually. The durations of platelet count more than 50×109/L in 3 cycles were 13, 7 and 10 days respectively. No increase of WBC count and Hb level occurred. No liver and kidney function damage, abnormal coagulation functions or thrombosis developed during the treatment. rhTPO antibodies were not detectable. The result indicated that rhTPO could transiently increase peripheral platelet counts of the patient with chronic refractory ITP. It was uncertain why peak platelet counts declined and durations of platelet count more than 50×109/L shortened when multiple cycles of rhTPO were given.

Single and Multiple Oral Doses of LGD-4665, a Small Molecule Thrombopoietin Receptor Agonist, Increase Platelet Counts in Healthy Male Subjects

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1298-1298 ◽  
Author(s):  
Zofia E. Dziewanowska ◽  
Richard M. Matsumoto ◽  
J.K. Zhang ◽  
Kristine Schindler ◽  
Gordon Loewen ◽  
...  
Keyword(s):  
Platelet Count ◽  
Single Dose ◽  
Multiple Dose ◽  
Receptor Agonist ◽  
Healthy Male ◽  
Post Dose ◽  
Dose Administration ◽  
Platelet Counts ◽  
Multiple Dose Administration ◽  
Male Subjects

Abstract LGD-4665, an oral thromobopoietin receptor agonist, is being developed as a new generation small molecule thrombopoietin (TPO) mimetic. LGD-4665 is a highly selective and potent agonist of the TPO receptor and induces differentiation and proliferation of megakaryocytes. A single-center, randomized, placebo-controlled, double-blind, escalating dose group study was conducted to assess the pharmacodynamics, pharmacokinetics (PK), and safety of LGD-4665 in healthy male subjects after single and multiple doses. In the single dose phase of the study, 5 dose cohorts of 6 subjects each were randomized at a ratio of 2:1 (LGD-4665: Placebo). LGD-4665 doses of 1, 5, 10, 20, and 40 mg were escalated sequentially. In the multiple dose phase, 8 subjects received 5 mg of study drug or placebo at a ratio of 3:1, respectively, once daily for 14 days. Clinical assessments were conducted for 21 and 35 days following treatment initiation in the single and multiple dose phases, respectively. Platelet count increases were determined as the maximal observed increase in post-dose platelet value relative to baseline, expressed both as absolute value and percent increase. Following single dose administration, a statistically-significant (p=0.011) platelet count increase compared to placebo was observed following a 40 mg LGD-4665 dose. In subjects receiving this dose, individual maximum increases in platelet counts ranged between 53 and 83 x1000/μL (mean = 65 x1000/μL; 29% increase from baseline). Following multiple dose administration of 5 mg daily for 14 days, increases in platelet counts over baseline were observed in all drug-treated subjects (n=6) with a mean maximal increase from baseline of 43%. From PK measurements, a dose-proportional increase in systemic exposure after single doses of LGD-4665 was observed among the dose groups. Mean area-under-the-curve from time zero to infinity (AUC0-inf) increased from 2.88 to 155 μg·h/mL following single doses of 1 to 40 mg, respectively, with AUC0–24h values of 0.43 – 25.3 μg·h/mL. Maximum LGD-4665 concentrations (Cmax) increased from 0.029 to 1.56 μg/mL following administration of 1 to 40 mg single doses, respectively. In the multiple phase, 5 mg daily doses for 14 days resulted in a mean Cmax of 0.83 μg/mL and the Cmax were reached at 4 hours post dose. The mean steady-state AUC0 to 24h was 17.4 μg·h/mL. Overall, LGD-4665 was safe and well tolerated at all dose levels tested during both phases of the study. All AEs were appraised as mild to moderate. The majority of AEs were not related to LGD-4665 and no apparent dose-relationship was observed. No serious AEs were reported. No subjects discontinued the study due to AEs. No clinically significant laboratory abnormalities, effects on electrocardiograms and vital signs were observed. In summary, LGD-4665 increase platelet counts following single and multiple dose administration and was well tolerated.

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