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PHARMACOKINETICS AND PHARMACODYNAMICS

Pharmacodynamics and Pharmacokinetics of AMG 531, a Thrombopoiesis-Stimulating Peptibody, in Healthy Japanese Subjects: A Randomized, Placebo-Controlled Study

Yuji Kumagai, MD, PhD, Tomoe Fujita, MD, PhD, Machiko Ozaki, MD, Kunihiko Sahashi, Masayuki Ohkura, Tomoko Ohtsu, MD, PhD, Yoshihiro Arai, Yusuke Sonehara and Janet L. Nichol

From the Clinical Investigation Center, Kitasato University East Hospital, Kanagawa, Japan (Y. Kumagai, T. Fujita, M. Ozaki, K. Sahashi); Amgen Limited, Tokyo, Japan (M. Ohkura, T. Ohtsu, Y. Arai, Y. Sonehara); and Amgen, Thousand Oaks, California (J. L. Nichol).

Address for correspondence: Dr Yuji Kumagai, Kitasato University East Hospital, 2-1-1, Asamizodai, Sagamihara, Kanagawa, Japan 228-8520.


   ABSTRACT
TOP
 ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 ACKNOWLEDGEMENTS
 REFERENCES
 
AMG 531 is a novel thrombopoiesis-stimulating peptibody being investigated for the treatment of chronic immune thrombocytopenic purpura. This double-blind, phase I study evaluated the safety, pharmacodynamics, and pharmacokinetics of AMG 531 in healthy Japanese men. Thirty subjects were randomly assigned 4:1 (AMG 531/placebo) to receive 1 dose of AMG 531 (0.3, 1, or 2 µg/kg) or placebo by subcutaneous injection; subjects were evaluated for 6 weeks. AMG 531 was generally well tolerated, with adverse events similar to placebo. Treatment-related adverse events (headache, "feeling hot," malaise) were reported for 5 of 24 AMG 531-treated subjects. Platelets generated after exposure to AMG 531 functioned normally. Four of 8 subjects receiving 1 µg/kg and 7 of 8 receiving 2 µg/kg had platelet count increases ≥1.5-fold over baseline, an effect similar to that seen in non-Japanese subjects. Serum AMG 531 concentrations were below the lower limit of quantification in all but 2 subjects receiving 2 µg/kg.

Key Words: Thrombopoiesis • thrombopoietin • immune thrombocytopenic purpura • platelets • platelet aggregation • AMG 531

Immune thrombocytopenic purpura (ITP) is an autoimmune disorder usually characterized by platelet destruction caused by antiplatelet autoantibodies.1-4 It may have a serious impact on patients' health, substantially increasing the risk of spontaneous bleeding and, rarely, intracranial hemorrhage. For patients who have this disorder, ITP and its treatment may reduce life expectancy5 and health-related quality of life.6

Approximately 500 to 2000 new cases of chronic ITP are diagnosed each year in Japan,7,8 a rate of incidence similar to that seen in Western countries.8 In adults, ITP occurs approximately twice as frequently in women as in men, although the difference between sexes diminishes as the age of onset increases.1,9 Immune thrombocytopenic purpura rarely remits spontaneously.10 Current therapies for ITP include corticosteroids, intravenous immunoglobulin (IVIg), and splenectomy.10,11 Helicobacter pylori eradication therapies may also be used to treat ITP.12,13 Patients refractory to these therapies may receive other treatments, either alone or in combination, including pulsed dexamethasone, danzanol, cytotoxic agents, colchicine, azithropine, interferon-{alpha}, protein A-immunoadsorption, splenic radiation, and partial splenic embolization. Evidence supporting these treatments is limited, and side effects may be considerable.10,11

AMG 531 is a novel recombinant protein (approximately 60 kDa) expressed in Escherichia coli that is being investigated for the treatment of chronic ITP. Although most current treatments for chronic ITP act by decreasing platelet destruction or suppressing the production of antiplatelet antibodies, AMG 531 targets megakaryocyte and platelet development through the same pathway as endogenous thrombopoietin (eTPO).14 AMG 531 has no sequence homology to eTPO, thereby avoiding the development of cross-reacting antibodies.14,15 AMG 531 has 5 domains: 4 peptide-containing domains that bind to the receptor for endogenous thrombopoietin (Mpl) and an Fc domain that increases the half-life of AMG 531 in circulation.

In a cross-sectional study of patients with decreased platelets, samples from thrombocytopenic patients were measured for eTPO concentrations. Despite thrombocytopenia, eTPO concentrations in patients with ITP were within the normal range in 74% of cases and were lower than the levels predicted for the patients with aplastic anemia.16 This study of an exogenous Mpl ligand elucidated the potential of AMG 531 as a therapeutic option for increasing platelet counts in ITP patients. In phase I and II studies in the United States and Europe, AMG 531 was associated with a dose-dependent increase in platelet counts in healthy volunteers and in patients with chronic ITP.14,17,18

The pharmacodynamics and pharmacokinetics of AMG 531 have been evaluated in 32 healthy non-Japanese male subjects,18 but its pharmacokinetic and pharmacodynamic properties in Japanese subjects are not known. This single-center, randomized, double-blind, placebo-controlled, phase I study was designed to evaluate various doses of AMG 531 in healthy Japanese men. The study assessed the safety and tolerability (including effects on platelet aggregation and platelet function), pharmacodynamic response (effect on platelet counts), and pharmacokinetic profiles in this population.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 CONCLUSIONS
 ACKNOWLEDGEMENTS
 REFERENCES
 
Study Design
This phase I double-blind, placebo-controlled study in healthy adult Japanese men was conducted according to the principles of the Japanese Ministry of Health, Labor, and Welfare and the International Conference on Harmonization regulations and guidelines. The study protocol and all amendments were approved by the institutional review board at Kitasato University East Hospital, Kanagawa, Japan. Written informed consent was obtained from all subjects. The primary objective of the study was to assess the safety and tolerability of a single subcutaneous administration of AMG 531. The secondary objective was to assess the pharmacokinetic and pharmacodynamic profiles of AMG 531. The study schema is shown in Figure 1.


Figure 1
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  		Figure 1. Study design and treatment schema. PK, pharmacokinetics; PD, pharmacodynamics. *0.3, 1, or 2 µg/kg.

 
Subjects were randomly assigned 4:1 (AMG 531/placebo) to each of the first 3 dose cohorts (0.3, 1, and 2 µg/kg). Dose escalation from 0.3 to 1 µg/kg and from 1 to 2 µg/kg was to occur if fewer than 4 subjects achieved a >2-fold increase from baseline in 2 consecutive platelet counts; dose escalation from 2 to 3 µg/kg was planned if fewer than 2 subjects achieved a >2-fold increase from baseline in 2 consecutive platelet counts. Following these rules, dose escalation was stopped at 2 µg/kg, and a planned fourth cohort (3 µg/kg) was not initiated. After screening, subjects were hospitalized on study days -1 through 22 and followed in clinic visits on days 29, 36, and 43. A single dose of AMG 531 or placebo was administered on day 1.

Primary endpoints included the incidence of adverse events; clinically significant changes in platelet counts or other laboratory values, electrocardiograms, or vital signs; and the development of antibodies to AMG 531 or eTPO. Secondary endpoints included pharmacodynamic response, pharmacokinetic parameters, and changes in platelet aggregation.

Treatments
AMG 531 was supplied as a sterile, lyophilized powder for reconstitution with 1.2 mL of sterile water for injection. The placebo was identical to the active formulation except that it contained no AMG 531.

Subjects
The subjects were healthy Japanese men from 20 through 50 years of age. They were required to have a body mass index (BMI) in the normal range (≥18.5 and <25 kg/m2, according to World Health Organization criteria) and 2 platelet counts (at screening and on day -1) in the range of 150 to 350 x 109/µL. They were also required to have negative test results for hepatitis B surface antigen, hepatitis C virus antibody, human immunodeficiency virus antibody, and syphilis.

Prospective subjects were excluded if they had an unstable medical condition, defined as a history of hospitalization within 4 weeks of day 1 or surgery within 24 weeks of day 1, clinically significant systemic disease requiring pharmacologic treatment, or abnormal findings requiring in-depth investigation. They were also excluded if they had clinical laboratory values (chemistry, hematology, or urinalysis) or vital signs exceeding normal physiological variation; abnormal electrocardiogram findings; or history of cardiovascular disease, bleeding or coagulation disorders, malignancy, or prior use of any thrombopoietic agent. Prospective subjects with a history of smoking within the year before day 1 were also excluded.

Smoking was not permitted at any time. No use of any over-the-counter, herbal, or prescription medications within 3 weeks before dosing or during the study was permitted, except for topical dermal medications or eye drops without systemic action. Subjects were required to abstain from alcoholic beverages from the day before hospitalization (day -2) until discharge (day 22). After discharge, subjects were required to limit alcohol intake to ≤2 drinks per week until the end of the study; no alcohol was permitted in the 8 hours before each weekly outpatient laboratory test. In addition, food or drink containing fat was not permitted in the 8 hours before blood sampling for platelet aggregation on days -1, 2, 15, and 43.

Assessments
The safety and tolerability of AMG 531 were assessed by means of reported adverse events and laboratory evaluations (hematology, clinical chemistry, coagulation, platelet aggregation, iron status, determination of antibodies to AMG 531, and urinalysis). Platelet counts, time to the maximum platelet count, and duration of platelet count elevation were used to assess pharmacodynamics.

Serum AMG 531 concentration-time profiles determined by the use of a validated enzyme-linked immunosorbent assay (ELISA) were used to assess pharmacokinetics. A bridging immunoassay method was used to quantify AMG 531 in the serum. AMG 531 containing standards, quality controls, and test samples in the serum were allowed to react with a capture antibody coated to microtiter wells. After washing away any unbound AMG 531, a biotinylated secondary antibody was added to the wells to form a bridge; a washing step followed. Horseradish peroxidise-labeled streptavidin was then added, and a final washing step was performed. A substrate solution containing tetramethylbenzidine and hydrogen peroxide was added to produce a colorimetric signal, which was proportional to the amount of AMG 531 bound by the capture reagent in the initial step. Color development was stopped using an acid solution, and optical density was measured at 450 nm. The quantification range for this assay was 18 to 500 pg/mL.

In the platelet aggregation studies, the platelet count of platelet-rich plasma was adjusted to between 15 x 109/L and 40 x 109/L by dilution in the subject's own platelet-poor plasma. Concentrations of 0.2 and 2 µg/mL collagen and 0.5 and 2 µmol/L adenosine diphosphate were used as reagents. Percent of platelet aggregation and percent change in platelet aggregation were examined on day -1, day 2, day 15, and at the end of the study.

Immunogenicity was assessed in stages. A biosensor immunoassay (Biacore 3000, Biacore AB, Uppsala, Sweden) was used to detect binding antibodies specific for AMG 531, the biologically active mimetic peptide portion of AMG 531 (TMP), or eTPO using a surface plasmon resonance-based screening technique. The assay was validated for threshold, sensitivity, net binding cut point, and stability of the immobilized surfaces.19,20 At the limit of quantitation (LOQ), the human assay is capable of detecting 200 ng/mL of anti-eTPO positive control antibody and 400 ng/mL of anti-AMG 531 control antibody in neat serum. The drug tolerance at the LOQ concentration of the Biacore assay was 1 µg/mL. If binding antibodies were detected in the biosensor immunoassay, a cell-based bioassay was used to detect the presence of neutralizing antibodies. Samples that demonstrated reactivity in that assay were tested for specificity and protein-G depletion to confirm the presence of a specific, antibody-mediated response. These bioassays were validated for threshold and sensitivity.21 The AMG 531 screening assay is capable of detecting 400 ng/mL of anti-AMG 531 neutralizing antibodies in neat serum. The drug tolerance at the assay sensitivity is 25 ng/mL for detecting neutralizing antibodies against AMG 531 and 6.25 ng/mL for detecting neutralizing antibodies against eTPO. Following protein-G depletion, the assay was capable of detecting 500 ng/mL of anti-AMG 531 antibodies.

Data for all assessments were summarized with descriptive statistics.


   RESULTS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 CONCLUSIONS
 ACKNOWLEDGEMENTS
 REFERENCES
 
Thirty young, healthy subjects were enrolled into the 0.3-, 1-, and 2-µg/kg cohorts; 8 subjects received AMG 531, and 2 received placebo in each cohort. Treatment groups were comparable with respect to demographics and baseline characteristics (Table I). The mean age was 28.5 ± 6.6 years for subjects assigned to receive AMG 531 and 26.5 ± 5.3 years for subjects assigned to placebo. The mean BMI was 21.5 ± 1.6 kg/m2 in the AMG 531 group and 21.1 ± 1.8 in the placebo group.


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  		Table I Demographics and Baseline Characteristics

 

Safety and Tolerability
No serious, severe, or clinically significant adverse events were reported. The most commonly reported adverse events among subjects who received AMG 531, without regard to relationship to treatment, were lower abdominal pain, diarrhea, headache, nasopharyngitis, and transient elevated liver enzymes (Table II). Five of 24 subjects who received AMG 531 had treatment-related adverse events (headache, migraine without aura, "feeling hot," and/or malaise), versus 0 of 6 subjects receiving placebo. All of these treatment-related events were mild in severity and required no medical intervention. Transient values outside the normal range for clinical laboratory variables were observed sporadically. None were considered to be treatment related, and none required medical intervention.


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  		Table II Adverse Events Reported in 2 or More Subjects Treated With AMG 531

 

No neutralizing antibodies against AMG 531 or eTPO were detected in any subject at any time during the study. In the 24 subjects who received AMG 531, binding antibodies against eTPO were observed at baseline, at week 15, and at the end of the study for 4 subjects and only at the end of the study for 1 subject. One subject exhibited binding antibodies to both AMG 531 and TMP baseline, week 15, and at the end of the study. Of the 6 subjects who received placebo, 1 had a low level of binding antibodies to eTPO at baseline. In subjects who developed an antibody response, most responses were not markedly higher than baseline levels.

There was no detectable enhancement or reduction in aggregatory response of platelets in subjects treated with either AMG 531 or placebo. No differences in platelet aggregation were observed when pretreatment samples were compared with post-treatment samples or when samples from subjects treated with AMG 531 were compared with samples from placebo-treated subjects. Figure 2 displays platelet aggregation percentages in blood samples taken from subjects treated with AMG 531 2 µg/kg or placebo and exposed to the higher concentration of the 2 reagents (2 µg/mL collagen and 2 µmol/L adenosine phosphate).


Figure 2
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  		Figure 2. Changes in platelet aggregation over time after a single administration of placebo or AMG 531 2 µg/kg.

 
Pharmacodynamics
Of 8 subjects who received the 1-µg/kg dose, 4 achieved a ≥1.5 fold increase in platelet count, and 1 achieved a ≥2-fold increase. Of 8 subjects who received the 2-µg/kg dose, 7 achieved a ≥1.5-fold platelet count increase, and 3 achieved a ≥2-fold increase. The maximum platelet count for subjects who received the 1- or 2-µg/kg dose was reached on day 12 (±2 days). Platelet count elevation (defined as a ≥1.3-fold increase over baseline for 2 consecutive days) lasted from 2 to 15 days for 7 of 8 subjects who received the 1-µg/kg dose and from 6 to 16 days for all 8 subjects who received the 2-µg/kg dose. A platelet response was not observed with the 0.3-µg/kg dose or placebo.

The mean platelet counts increased with increasing doses of AMG 531 (Figure 3). These results were similar to those seen in non-Japanese subjects (Figure 4).18 The maximum platelet counts increased in a dose-dependent manner (Table III) and were 260.8 x 109/L, 402.0 x 109/L, and 465.5 x 109/L for the 0.3-, 1-, and 2-µg/kg dose groups, respectively. Mean area under the platelet-time curve (AUCplt) values increased in a dose-dependent manner (Table III) and were 8%, 28%, and 34% higher than placebo for the 0.3-, 1-, and 2-µg/kg doses, respectively. Ratios of maximum-to-baseline platelet count were similar for Japanese subjects in this study and non-Japanese subjects in the Wang et al study (Figure 5).18


Figure 3
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  		Figure 3. Mean platelet counts in healthy Japanese subjects. Error bars indicate standard deviation (SD). The dashed lines show the normal platelet count range in humans (150 to 450 x 109/L).

 

Figure 4
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  		Figure 4. Mean platelet counts in healthy non-Japanese subjects.18 Error bars indicate standard deviation (SD). The dashed lines show the normal platelet count range in humans (150 to 450 x 109/L). Reproduced with permission from Wang B, Nichol JL, Sullivan JT. Pharmacodynamics and pharmacokinetics of AMG 531, a novel thrombopoietin receptor ligand. Clin Pharmacol Ther. 2004;76:628-638.

 

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  		Table III Summary of Pharmacodynamic Parameters of AMG 531

 

Figure 5
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  		Figure 5. Ratios of maximum to baseline platelet count: Japanese versus non-Japanese subjects. Patient values are shown by points. The box for each dose shows the segment containing 50% of the data, divided into the first and third quartiles. The plot for non-Japanese subjects is from Amgen data on file.

 

Pharmacokinetics
Because AMG 531 has not been detected in the serum of human subjects receiving subcutaneous doses <1 µg/kg, pharmacokinetic analysis was conducted only for the 10 subjects in the 2-µg/kg cohort (8 treated with AMG 531 and 2 with placebo). Serum AMG 531 concentrations were below the lower limit of quantitation (LLOQ) (18 pg/mL) for both placebo-treated subjects and for 6 of 8 subjects who received AMG 531 2 µg/kg. One subject had an AMG 531 serum concentration of 20.8 pg/mL at 24 hours after dosing, which fell to 18.9 pg/mL at 30 hours. Another subject had a serum concentration of 47.6 pg/mL at 24 hours after dosing, which declined to 43.4 pg/mL at 30 hours, 24.5 at 36 hours, and 24.0 pg/mL at 48 hours.


   DISCUSSION
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
CONCLUSIONS
 ACKNOWLEDGEMENTS
 REFERENCES
 
Single doses of AMG 531 at up to 2.0 µg/kg were well tolerated. No serious or severe adverse events were reported in this study at any dose administered. Four of 8 subjects who received 1.0 µg/kg of AMG 531 achieved a >1.5-fold increase in platelet count over baseline (2.35-fold; 568 x 109/L at peak). Seven of 8 subjects who received 2.0 µg/kg of AMG 531 achieved a >1.5-fold increase in platelet count over baseline, and 3 subjects achieved a >2-fold increase in platelet count over baseline (2.66-fold; 587 x 109/L at peak) with the 2.0-µg/kg dose. The pharmacodynamic responses of the Japanese subjects in this study were similar to those seen in previous studies of AMG 531 in non-Japanese subjects.

As in the Wang et al study,18 AMG 531 resulted in a dose-dependent increase in platelet counts at doses ≥1 µg/kg in this study. As shown in Figures 3 through 5, the overall similarity in platelet response was consistent between healthy Japanese subjects in this study and healthy non-Japanese subjects in the Wang et al phase I study.18 The safety profiles and pharmacodynamic responses of the Japanese subjects were similar to those seen with the same doses of AMG 531 in previous studies of AMG 531 in non-Japanese subjects.

There were no significant detectable changes in the aggregatory response of platelets following administration of AMG 531 at any dose or placebo. Despite the suggested possibility of platelet dysfunction in subjects with essential thrombocythemia,22 the platelets generated by the administration of AMG 531 in this study show normal platelet function. This result was similar to that obtained in the study of pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF), in which no significant differences were observed in platelet aggregation response.23

No severe or serious adverse events were reported in subjects who received AMG 531. The most frequently reported adverse event in subjects who received AMG 531 was headache (13% vs 0% of subjects who received placebo) (Table II). AMG 531 was generally well tolerated at all doses. No neutralizing antibodies to AMG 531 or eTPO were detected. Two subjects had serum AMG 531 concentrations above the LLOQ; both of these subjects had quantifiable serum AMG 531 concentrations at 24 hours postdose through at least 30 hours. These results were consistent with those observed in the Wang et al study.18

Although no subjects in this study exhibited neutralizing antibodies to AMG 531, 6 subjects exhibited binding antibodies to AMG 531, TMP, and/or eTPO. Five of these 6 subjects had low levels of preexisting binding antibodies at baseline. In the Wang et al study,18 no antibodies to eTPO or neutralizing antibodies to AMG 531 were detected; low-level binding antibodies to AMG 531 were detected in 1 subject who received AMG 531 at 10 µg/kg (5 times the highest dose administered in this study). Although these results appear to suggest a difference between the antibody response of these Japanese and non-Japanese subjects, it is likely that no real difference exists. Although both studies used the same platform for immunoassay binding antibody detection, several improvements have made the assay more sensitive and more specific since the Wang et al study was conducted; these improvements include a high-affinity positive control, the addition of a confirmatory step, and a protein-G depletion test for specificity.

Similarly, the high incidence of preexisting antibodies can probably be attributed to the high sensitivity of the Biacore screening assay, which is capable of detecting low-affinity endogenous cross-reactive antibodies. The fact that most of these subjects did not develop an antibody response markedly above their baseline responses indicates that the observed response is unlikely to be attributable to AMG 531. The significance of the preexisting antibodies is unclear. Their presence can potentially be explained by molecular mimicry (similar structures shared by molecules from dissimilar genes or by their protein products).24,25 To date, no safety concerns related to the activity of the binding antibodies have been identified.


   CONCLUSIONS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
ACKNOWLEDGEMENTS
 REFERENCES
 
Single doses of AMG 531 at up to 2.0 µg/kg were well tolerated, and no serious or severe adverse events were reported in this study at any dose administered. The pharmacodynamic responses of Japanese men were similar to those seen in previous studies of AMG 531 in non-Japanese subjects. AMG 531, a novel thrombopoietin receptor ligand, was effective at increasing platelet counts in healthy subjects when administered as a single subcutaneous dose at ≥1 µg/kg. The platelets generated after exposure to AMG 531 at any dose functioned normally compared with platelets generated after exposure to placebo, as well as with pretreatment platelets.


   ACKNOWLEDGEMENTS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 ACKNOWLEDGEMENTS
REFERENCES
 
Financial disclosure: The authors thank Sue Hudson for assistance in writing the manuscript on behalf of Amgen, Inc, Thousand Oaks, California. Y. Kumagai is a consultant to Amgen Limited, Japan. M. Ohkura, T. Ohtsu, Y. Arai, and Y. Sonehara are employees of Amgen Limited, Japan. J. L. Nichol is an employee of Amgen, Inc, USA. This study was funded by Amgen Limited, Japan.

DOI: 10.1177/0091270007306563


   REFERENCES
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 ACKNOWLEDGEMENTS
 REFERENCES
 

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