scholarly journals Intrapulmonary Pharmacokinetics of GSK2251052 in Healthy Volunteers

2013 ◽  
Vol 57 (7) ◽  
pp. 3334-3339 ◽  
Author(s):  
David Tenero ◽  
Gary Bowers ◽  
Keith A. Rodvold ◽  
Apurva Patel ◽  
Milena Kurtinecz ◽  
...  
Keyword(s):  
Healthy Volunteers ◽  
Vital Signs ◽  
Volume Of Distribution ◽  
Repeat Dose ◽  
Dose Administration ◽  
Epithelial Lining Fluid ◽  
Dose Cohort ◽  
The Mean ◽  
Safety Assessments ◽  
Clinically Significant

ABSTRACTThe plasma and intrapulmonary pharmacokinetics (PK) of intravenous (i.v.) GSK2251052, a novel boron-containing antimicrobial, were evaluated in healthy adult subjects. Thirty subjects underwent bronchoscopy and timed bronchoalveolar lavage (BAL) either following a single dose (cohort 1) or after 5 twice-daily doses (cohort 2) of 1,500 mg GSK2251052 i.v. Serial PK and safety assessments were obtained throughout the study. Bronchoscopy was performed on a single occasion in each subject at 2, 6, or 12 h after start of infusion. Noncompartmental analysis was performed to calculate PK parameters. Thirty subjects completed the study. The mean clearance (CL), volume of distribution at steady state (Vss), and half-life (t1/2) values were 22 liters/h, 231 liters, and 10.7 h, respectively. Approximately 30% of the dose was excreted unchanged in urine. The GSK2251052 concentrations in epithelial lining fluid (ELF) and alveolar macrophages (AM) were approximately 50% and 500 to 600%, respectively, compared to the concentration in plasma. the GSK2251052 exposures in ELF and AM were comparable following single- and repeat-dose administration. The most frequently reported drug-related adverse event (AE) was mild to moderate infusion site reactions (7 subjects) that occurred primarily in the repeat-dose cohort. No serious drug-related AEs or clinically significant trends in laboratory values, vital signs, or electrocardiograms were observed. GSK2251052 given as a 1,500-mg infusion was generally tolerated following single- or repeat-dose administration. GSK2251052 distributes into both the ELF and AM of healthy volunteers, which supports further study in patients with pneumonia.

Effects of a Pneumatic Tube System on Routine and Novel Hematology and Coagulation Parameters in Healthy Volunteers

2007 ◽  
Vol 131 (2) ◽  
pp. 293-296
Author(s):  
Alexander Kratz ◽  
Raneem O. Salem ◽  
Elizabeth M. Van Cott
Keyword(s):  
Healthy Volunteers ◽  
Prothrombin Time ◽  
Partial Thromboplastin Time ◽  
Activated Partial Thromboplastin Time ◽  
Tube System ◽  
Blood Samples ◽  
Pneumatic Tube ◽  
The Mean ◽  
Clinically Significant ◽  
Pneumatic Tube System

Abstract Context.—Technologic advances affecting analyzers used in clinical laboratories have changed the methods used to obtain many laboratory measurements, and many novel parameters are now available. The effects of specimen transport through a pneumatic tube system on laboratory results obtained with such modern instruments are unclear. Objective.—To determine the effects of sample transport through a pneumatic tube system on routine and novel hematology and coagulation parameters obtained on state-of-the-art analyzers. Design.—Paired blood samples from 33 healthy volunteers were either hand delivered to the clinical laboratory or transported through a pneumatic tube system. Results.—No statistically significant differences were observed for routine complete blood cell count and white cell differential parameters or markers of platelet activation, such as the mean platelet component, or of red cell fragmentation. When 2 donors who reported aspirin intake were excluded from the analysis, there was a statistically, but not clinically, significant impact of transport through the pneumatic tube system on the mean platelet component. There were no statistically significant differences for prothrombin time, activated partial thromboplastin time, waveform slopes for prothrombin time or activated partial thromboplastin time, fibrinogen, or fibrin monomers. Conclusions.—Although further study regarding the mean platelet component may be required, transport through a pneumatic tube system has no clinically significant effect on hematology and coagulation results obtained with certain modern instruments in blood samples from healthy volunteers.

Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Anti-Vwf Nanobody® ALX-0681 After Single and Multiple Subcutaneous Administrations to Healthy Volunteers.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1063-1063 ◽  
Author(s):  
Khalid Abd-Elaziz ◽  
Pieter W. Kamphuisen ◽  
Christophe Lyssens ◽  
Mariska Reuvers ◽  
Izaak den Daas ◽  
...  
Keyword(s):  
Single Dose ◽  
Platelet Aggregation ◽  
Healthy Volunteers ◽  
Dose Level ◽  
Multiple Dose ◽  
Phase I Trial ◽  
Post Dose ◽  
Dose Cohort ◽  
Clinically Significant ◽  
Dose Levels

Abstract Abstract 1063 Poster Board I-85 ALX-0681 is a humanized bivalent Nanobody®, that binds to the A1 domain of von Willebrand factor (vWF) and hence blocks its interaction with platelet receptor GPIb-IX-V. Given its mode of action, ALX-0681 could provide an alternative treatment option for thrombotic thrombocytopenic purpura (TTP), a rare and life-threatening condition characterized by systemic platelet aggregation in the microcirculation mediated by activated vWF multimers. The goal of this Phase I trial in healthy volunteers was to determine the maximum tolerated dose (MTD) or biologically effective dose (BED) and the Phase II dosing and scheduling of ALX-0681, in order to support the further clinical development of ALX-0681 in TTP patients. In total, 36 healthy volunteers were included in this randomized, placebo-controlled study to evaluate the safety of single ascending doses and multiple doses of ALX-0681 administered subcutaneously (s.c.) (Table 1). Table 1 Dosing schedule for Phase I trial with ALX-0681 Cohort Dose (mg) Number of daily doses Subjects receiving ALX-0681 Subjects receiving placebo Single dose Cohort 1 2 1 3 1 Cohort 2 4 1 3 1 Cohort 3 8 1 3 1 Cohort 4 16 1 3 1 Cohort 5 10 1 3 1 Multiple dose Cohort 6 10 7 6 2 Cohort 7 10 14 6 2 Study endpoints included safety (dose limiting toxicities, adverse events (AEs) and immunogenicity), pharmacokinetics (PK), pharmacodynamics (PD) and pharmacological efficacy of ALX-0681. The latter endpoint was addressed by measuring the ristocetin cofactor (RICO) biomarker, reflecting vWF mediated inhibition of platelet aggregation. ALX-0681 was safe and well tolerated at all dose levels (Table 2). One unrelated SAE (meniscus lesion) occurred. The number of observed signs of bleeding and bruises increased with increasing treatment duration. However, all these events were of mild intensity. No signs of immunogenicity were observed for a minimum of 45 days after the last injection. Table 2 Summary of main safety results (number (%) of subjects with event) Dose level Subjects (n) AE SAE Bleeding Hematoma at injection site Hematoma at blood sampling site Other hematoma Single dose 2 mg 3 2 (67) 0 (0) 1 (33) 0 (0) 1 (33) 0 (0) 4 mg 3 2 (67) 0 (0) 1 (33) 0 (0) 0 (0) 0 (0) 8 mg 3 3 (100) 0 (0) 0 (0) 0 (0) 1 (33) 0 (0) 16 mg 3 3 (100) 0 (0) 0 (0) 0 (0) 0 (0) 1 (33) 10 mg 3 1 (33) 0 (0) 0 (0) 0 (0) 1 (33) 0 (0) Placebo 5 3 (60) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) Multiple dose 10 mg (7d) 6 6 (100) 1 (17) 5 (83) 1 (17) 0 (0) 3 (50) Placebo (7d) 2 2 (100) 0 (0) 1 (50) 0 (0) 1 (50) 0 (0) 10 mg (14d) 6 6 (100) 0 (0) 5 (83) 5 (83) 4 (67) 5 (83) Placebo (14d) 2 2 (100) 0 (0) 1 (50) 0 (0) 0 (0) 0 (0) PK analysis showed a rapid increase in ALX-0681 plasma concentration (tmax = 4-10 h post dose), followed by a slow elimination phase (t1/2 = 10-78 h). All subjects dosed with ALX-0681 at 8 mg or higher showed complete inhibition of RICO activity to < 20% with an onset of 1-6 h post dose. This inhibition was maintained until 12-360 h post dose, depending on the dose level (Table 3). Overall, 20 (74%) and 17 (63%) of ALX-0681 treated subjects experienced a drop in vWF and FVIII levels below 50% of pre-dose levels, respectively. These events were all transient and not clinically significant. Table 3 Summary of main PD results (number (%) of subjects with event) Dose level Subjects (n) RICO < 20% vWF < 50% FVIII < 50% Subjects (%) Start (h)* Stop (h)* Single dose 2 mg 3 2 (67) 2-4 12-18 3 (100) 0 (0) 4 mg 3 2 (67) 4-6 18-36 1 (33) 1 (33) 8 mg 3 3 (100) 2-4 18-48 3 (100) 3 (100) 16 mg 3 3 (100) 1-4 48 0 (0) 2 (67) 10 mg 3 3 (100) 2-6 24-36 3 (100) 3 (100) Placebo 5 0 (0) NA NA 0 (0) 0 (0) Multiple dose 10 mg (7d) 6 6 (100) 2-4 168-192 5 (83) 3 (50) Placebo (7d) 2 0 (0) NA NA 0 (0) 0 (0) 10 mg (14d) 6 6 (100) 2-4 336-360 5 (83) 5 (83) Placebo (14d) 2 0 (0) NA NA 0 (0) 0 (0) * Time relative to first administration NA: not applicable In conclusion, ALX-0681 administered s.c. for up to 14 days was well tolerated and did not result in any clinically significant AEs. No local reactions, local intolerances or signs of clinically relevant bleeding were reported. The PD marker indicated complete inhibition of vWF mediated platelet aggregation following single daily s.c. injections of 10 mg, which was maintained over the 2 weeks treatment period. Multiple daily administration of s.c. injections of ALX-0681 did not result in an immunogenic reaction for a minimum of 45 days following completion of treatment. Based on the results of this study, ALX-0681 development will be advanced into a Phase II study in TTP patients to investigate the safety and efficacy of ALX-0681 in the target patient population. Disclosures: Abd-Elaziz: Ablynx NV: Consultancy. Kamphuisen:Ablynx NV: Consultancy. Lyssens:Ablynx NV: Employment. Reuvers:Ablynx NV: Consultancy. den Daas:Ablynx NV: Consultancy. Van Bockstaele:Ablynx NV: Employment. Vercruysse:Ablynx NV: Employment. Ulrichts:Ablynx NV: Employment. Baumeister:Ablynx NV: Employment. Crabbe:Ablynx NV: Employment. Compernolle:Ablynx NV: Employment. Holz:Ablynx NV: Employment.

Pharmacokinetics and Arteriovenous Differences in Clevidipine Concentration following a Short- and a Long-term Intravenous Infusion in Healthy Volunteers

2000 ◽  
Vol 92 (4) ◽  
pp. 993-1001 ◽  
Author(s):  
Hans Ericsson ◽  
Ulf Bredberg ◽  
Ulf Eriksson ◽  
Åse Jolin-Mellgård ◽  
Margareta Nordlander ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Steady State ◽  
Healthy Volunteers ◽  
Venous Blood ◽  
Volume Of Distribution ◽  
Pharmacokinetic Parameters ◽  
Blood Levels ◽  
Blood Concentrations ◽  
Arterial Blood ◽  
The Mean

Background Clevidipine is an ultra-short-acting calcium antagonist developed for reduction and control of blood pressure during cardiac surgery. The objectives of the current study were to determine the pharmacokinetics of clevidipine after 20-min and 24-h intravenous infusions, and to determine the relation between the arterial and venous concentrations and the hemodynamic responses to clevidipine in healthy volunteers. Methods Four volunteers received clevidipine for 20 min, and eight subjects were administered clevidipine intravenously for 24 h at two different dose rates. Arterial and venous blood samples were drawn for pharmacokinetic evaluation, and blood pressure and heart rate were recorded. Results A triexponential disposition model described the pharmacokinetics of clevidipine. The mean arterial blood clearance of clevidipine was 0.069l/kg-1/min-1 and the mean volume of distribution at steady state was 0.19 l/kg. The duration of the infusion had negligible effect on the pharmacokinetic parameters, and the context-sensitive half-time for clevidipine, simulated from the mean pharmacokinetic parameters derived after 24 h infusion at the highest dose, was less than 1 min. The arterial blood levels reached steady state within 2 min of the start of infusion and were about twice as high as those in the venous blood at steady state. The peak response preceded the peak venous concentration and was slightly delayed from the peak arterial blood concentration. Conclusion Clevidipine is a high clearance drug with a small volume of distribution, resulting in extremely short half-lives in healthy subjects. The initial rapid increase in the arterial blood concentrations and the short equilibrium time between the blood and the biophase suggest that clevidipine can be rapidly titrated to the desired effect.

Pharmacokinetics of Inhaled Liposome-encapsulated Fentanyl

1995 ◽  
Vol 83 (2) ◽  
pp. 277-284. ◽  
Author(s):  
Orlando R. Hung ◽  
Sara C. Whynot ◽  
John R. Varvel ◽  
Stephen L. Shafer ◽  
Michael Mezei
Keyword(s):  
Healthy Volunteers ◽  
Intravenous Administration ◽  
Venous Blood ◽  
Volume Of Distribution ◽  
Sustained Drug Release ◽  
Future Studies ◽  
Time To Peak ◽  
Drug Molecules ◽  
Peak Absorption ◽  
The Mean

Background Pulmonary administration of fentanyl solution can provide satisfactory but brief postoperative pain relief. Liposomes are microscopic phospholipid vesicles that can entrap drug molecules. Liposomal delivery of fentanyl has the potential to control the uptake of fentanyl by the lungs and thus provide sustained drug release. To demonstrate that inhalation of a mixture of free and liposome-encapsulated fentanyl can provide a rapid increase and sustained plasma fentanyl concentrations (CfenS), this study determined the pharmacokinetic profiles after the inhalation of free and liposome-encapsulated fentanyl in healthy volunteers. Methods After obtaining institutional approval and informed consent, ten healthy volunteers (five men, five women) were studied. Each subject received 200 micrograms intravenous fentanyl and inhaled 2,000 micrograms of free (50%) and liposome-encapsulated fentanyl (50%) on separate occasions. Frequent venous blood samples were collected, and CfenS were determined by radioimmunoassay. The pharmacokinetics and absorption characteristics of the inhaled mixture of free and liposome-encapsulated fentanyl were determined using moment analysis and least-squares numeric deconvolution. Results The mean (+/- SD) volume of distribution at steady-state and clearance of fentanyl after the intravenous administration were comparable to previous studies: 435 +/- 1821 and 0.584 +/- 0.209 l.min-1, respectively. The mean (+/- SD) peak Cfen was significantly greater for the intravenous administration compared to the aerosol mixture of free and liposome-encapsulated fentanyl (4.67 +/- 1.87 vs. 1.15 +/- 0.36 ng.ml-1). However, CfenS at 8 and 24 h after aerosol administration were greater compared to intravenous (0.25 +/- 0.14 and 0.12 +/- 0.16 ng.ml-1 for aerosol versus 0.16 +/- 0.10 and 0.05 +/- 0.06 ng.ml-1 for intravenous). The peak absorption rate, time to peak absorption, and bioavailability after inhalation were 7.02 (+/- 2.34) micrograms.min, -1(16) (+/- 8.0) min, and 0.12 (+/- 0.11), respectively. Conclusions The data suggest that this analgesic method offers a simple and noninvasive route of administration with a rapid increase of Cfen and a prolonged therapeutic fentanyl concentration. Future studies are required to determine the optimal liposome composition that would produce a sustained stable Cfen within analgesic therapeutic concentrations.

scholarly journals Bioavailability of Lumefantrine Is Significantly Enhanced with a Novel Formulation Approach, an Outcome from a Randomized, Open-Label Pharmacokinetic Study in Healthy Volunteers

2017 ◽  
Vol 61 (9) ◽  
Author(s):  
Jay Prakash Jain ◽  
F. Joel Leong ◽  
Lan Chen ◽  
Sampath Kalluri ◽  
Vishal Koradia ◽  
...  
Keyword(s):  
Single Dose ◽  
Healthy Volunteers ◽  
Solid Dispersion ◽  
Vital Signs ◽  
Study Drug ◽  
Relative Bioavailability ◽  
Open Label ◽  
Significant Treatment ◽  
Conventional Formulation ◽  
Clinically Significant

ABSTRACT The artemether-lumefantrine combination requires food intake for the optimal absorption of lumefantrine. In an attempt to enhance the bioavailability of lumefantrine, new solid dispersion formulations (SDF) were developed, and the pharmacokinetics of two SDF variants were assessed in a randomized, open-label, sequential two-part study in healthy volunteers. In part 1, the relative bioavailability of the two SDF variants was compared with that of the conventional formulation after administration of a single dose of 480 mg under fasted conditions in three parallel cohorts. In part 2, the pharmacokinetics of lumefantrine from both SDF variants were evaluated after a single dose of 480 mg under fed conditions and a single dose of 960 mg under fasted conditions. The bioavailability of lumefantrine from SDF variant 1 and variant 2 increased up to ∼48-fold and ∼24-fold, respectively, relative to that of the conventional formulation. Both variants demonstrated a positive food effect and a less than proportional increase in exposure between the 480-mg and 960-mg doses. Most adverse events (AEs) were mild to moderate in severity and not suspected to be related to the study drug. All five drug-related AEs occurred in subjects taking SDF variant 2. No clinically significant treatment-emergent changes in vital signs, electrocardiograms, or laboratory blood assessments were noted. The solid dispersion formulation enhances the lumefantrine bioavailability to a significant extent, and SDF variant 1 is superior to SDF variant 2.

Pharmacokinetics of Dirithromycin in Patients with Mild or Moderate Cirrhosis

1999 ◽  
Vol 43 (7) ◽  
pp. 1556-1559 ◽  
Author(s):  
Teresita Mazzei ◽  
Calogero Surrenti ◽  
Andrea Novelli ◽  
Maria Rosa Biagini ◽  
Stefania Fallani ◽  
...  
Keyword(s):  
Healthy Volunteers ◽  
Volume Of Distribution ◽  
Time Curve ◽  
Class A ◽  
Elimination Half ◽  
Class B ◽  
Child's Classification ◽  
Cirrhotic Patients ◽  
The Mean ◽  
Limited Basis

ABSTRACT The pharmacokinetics of dirithromycin were determined over a 72-h period following oral administration of a single 500-mg dose to 8 healthy volunteers and to 16 cirrhotic patients (8 patients with class A cirrhosis and 8 patients with class B cirrhosis according to Pugh’s & Child’s classification). Drug levels in plasma and urine were determined by microbiological assay. The mean maximum concentrations of drug in serum obtained 3 to 4 h after administration were 0.29 ± 0.22 mg/liter in volunteers and 0.48 ± 0.21 and 0.52 ± 0.38 mg/liter in patients with class A and class B cirrhosis, respectively. The elimination half-life (t 1/2β) was 23.3 ± 7.6 h in healthy subjects and 35.2 ± 11.8 h and 39.5 ± 11.0 h in patients with class A and class B cirrhosis, respectively. The mean area under the concentration-time curve (AUC) and t 1/2β were significantly higher in patients with class A and B cirrhosis than in healthy controls, while total and renal clearances were markedly reduced (P < 0.01). The time to the maximum concentration of drug in serum and the volume of distribution values appeared to be similar in all groups, and the mean recovery in urine at 72 h ranged from 3.7 to 5.7%, without significant differences among groups. These results demonstrate that some dirithromycin kinetic parameters are significantly different in cirrhotic patients in comparison to those in healthy volunteers. However, an increase in the t 1/2β or AUC, which is also observed with other semisynthetic macrolides (e.g., azithromycin), does seem to be not clinically relevant if one takes into account both the high therapeutic indices of these antibiotics and the usually short duration of therapy. Therefore, on the limited basis of single-dose administration, no modifications of dirithromycin dosage seem to be required even for patients with class B liver cirrhosis.

scholarly journals Sex correction improves the accuracy of clinical dopamine transporter imaging

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Emma A. Honkanen ◽  
Tommi Noponen ◽  
Risto Hirvilammi ◽  
Kari Lindholm ◽  
Riitta Parkkola ◽  
...  
Keyword(s):  
Sex Differences ◽  
Healthy Volunteers ◽  
Dopamine Transporter ◽  
Clinical Diagnostics ◽  
Reference Database ◽  
Mean Values ◽  
Healthy Elderly ◽  
Age Correction ◽  
The Mean ◽  
Clinically Significant

Abstract Background In clinical diagnostic imaging, dopamine transporter (DAT) SPECT scans are commonly evaluated using automated semiquantitative analysis software. Age correction is routinely implemented, but usually no sex correction of DAT binding is performed. Since there are sex differences in presynaptic dopaminergic function, we investigated the effect of DAT sex correction in a sample of healthy volunteers who underwent brain [123I]-FP-CIT SPECT. Methods Forty healthy elderly individuals (21 men and 19 women) underwent brain [123I]-FP-CIT SPECT, and each subject was examined clinically for motor and non-motor parkinsonian symptoms and signs. Regional specific DAT binding ratios (SBR = [ROI-occ]/occ) were calculated using age correction, and the results were compared to those in normal databases with and without sex correction. The level of regional abnormality was set at 2 standard deviations below the mean values of the reference databases. Results In the analysis without sex correction, compared to the mean ratio of the reference database, ten healthy individuals (8 men and 2 women) had abnormally low DAT binding ratios, and four individuals (3 men and 1 woman) had borderline low DAT binding ratios in at least one striatal region. When sex correction was implemented, the ratio of one individual was abnormal, and the ratio of one individual was borderline (both males). There were no clinically significant differences in motor or non-motor symptoms between healthy volunteers with abnormal and normal binding. Conclusions A considerable number of elderly healthy male subjects can be interpreted to be dopaminergically abnormal if no sex correction of DAT binding is performed. Sex differences in striatal dopaminergic function should be taken into account when DAT imaging is used to assist clinical diagnostics in patients with suspected neurological disorders.

scholarly journals Population pharmacokinetic study of isepamicin with intensive care unit patients.

1996 ◽  
Vol 40 (4) ◽  
pp. 983-987 ◽  
Author(s):  
M Tod ◽  
C Padoin ◽  
C Minozzi ◽  
J Cougnard ◽  
O Petitjean
Keyword(s):  
Intensive Care Unit ◽  
Intensive Care ◽  
Healthy Volunteers ◽  
Half Life ◽  
Volume Of Distribution ◽  
Multivariate Linear Regression Analysis ◽  
Icu Patients ◽  
Elimination Half Life ◽  
Elimination Half ◽  
The Mean

The pharmacokinetics (PK) of isepamicin, a new aminoglycoside, were studied in 85 intensive care unit (ICU) patients and were compared with those observed in 10 healthy volunteers. A parametric method based on a nonlinear mixed-effect model was used to assess population PK. Isepamicin was given intravenously over 0.5 h at dosages of 15 mg/kg once daily or 7.5 mg/kg twice daily. The data were fitted to a bicompartmental open model. Compared with healthy volunteers, the mean values of the PK parameters were profoundly modified in ICU patients: elimination clearance was reduced by 48%, the volume of distribution in the central compartment (Vc) was increased by 50%, the peripheral volume of distribution was 70% higher, the distribution clearance was 146% lower, and the elimination half-life was ca. 3.4 times higher. The interindividual variability in PK parameters was about 50% in ICU patients. Five covariates (body weight [BW], simplified acute physiology score [SAPS], temperature, serum creatinine level, and creatinine clearance [CLCR]) were tentatively correlated with PK parameters by multivariate linear regression analysis with stepwise addition and deletion. The variability of isepamicin clearance was explained by three covariates (BW, SAPS, and CLCR), that of Vc was explained by BW and SAPS, and that of the elimination half-life was explained by CLCR and SAPS. Simulation of the concentration-versus-time profile for 500 individuals showed that the mean peak (0.75 h) concentration was 18% lower in ICU patients than in healthy volunteers and that the range in ICU patients was very broad (28.4 to 95.4 mg/liter). Therefore, monitoring of the isepamicin concentration is in ICU patients is mandatory.

Single and Multiple Oral Doses of AKR-501 (YM477) Increase the Platelet Count in Healthy Volunteers.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 477-477 ◽  
Author(s):  
Robert E. Desjardins ◽  
Donna L. Tempel ◽  
Rudolph Lucek ◽  
David J. Kuter
Keyword(s):  
Platelet Count ◽  
Single Dose ◽  
Healthy Volunteers ◽  
Multiple Dose ◽  
In Vivo Models ◽  
Dose Cohort ◽  
Dose Study ◽  
The Mean ◽  
Oral Doses ◽  
To Receive

Abstract AKR-501 is an orally active thrombopoietin (TPO) receptor agonist that increases platelet production through stimulation of megakaryocyte proliferation and differentiation. The effect of AKR-501 in in vitro and in vivo models is additive with that of rhTPO. AKR-501 is a potential new therapy for use in the prevention or treatment of thrombocytopenia of various etiologies. We evaluated the safety, pharmacokinetics and pharmacodynamic activity of AKR-501 when administered as single and multiple oral doses to healthy volunteers. In the single dose study, 7 dose cohorts of 9 subjects each were randomized in a ratio of 2:1 to receive increasing doses (1, 3, 10, 20, 50, 75 and 100 mg) of AKR-501 or placebo. In the multiple dose study, 5 dose cohorts of 9 subjects each were to be randomized in a ratio of 2:1 to receive increasing doses (3, 10, 20, 50 and 100 mg) of AKR-501 or placebo administered daily for 14 days. All subjects were evaluated for safety and pharmacodynamic activity as assessed by peripheral blood platelet counts (PBPC). Dose escalation was stopped on Day 10 of dosing in the 3rd dose cohort (20 mg/day) when 6 of the volunteers exhibited a platelet count above 500,000/mL. The protocol defined endpoint of &gt;50% increase over baseline platelet count was achieved in 5 of 6 volunteers given a single dose of 100 mg, and in all 6 volunteers given daily doses of 10 mg for 14 days and 20 mg for 10 days. The drug was well tolerated in both the single and multiple dose studies with no serious drug-related adverse experiences reported at any dose. AKR-501 was consistently well absorbed exhibiting dose linear pharmacokinetics following single and multiple dose administration, and a serum half-life of approximately 16 hours. The mean observed Cmax following administration of single doses increased from 5.67 ng/mL at 1 mg to 388 ng/mL at 100 mg. The mean observed AUC increased from 174 ng·hr/mL at 1 mg to 11052 ng·hr/mL at 100 mg. Accumulation to steady state with multiple dosing was consistent with predictions based on a linear model and the single dose PK parameter estimates. There was a linear correlation of individual observed peak activity with corresponding Cmax (single-dose r2=0.70 p&lt;.0001, multiple-dose r2=0.67 p&lt;0.0001). The mean change from baseline PBPC for each dose cohort in the single-dose (Figure 1) and multiple-dose (Figure 2) studies are shown in the following graphs. Figure 1 Figure 1. Figure 2 Figure 2.

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