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Stem Cells, Vol. 18, No. 5, 360-365, September 2000
© 2000 AlphaMed Press

The Pharmacokinetics and Pharmacodynamics of GW395058, a Peptide Agonist of the Thrombopoietin Receptor, in the Dog, a Large-Animal Model of Chemotherapy-Induced Thrombocytopenia

Beth C. Casea, Marlene L. Haucka, Russell L. Yeagerb, Anita H. Simkinsb, Mark de Serresb, Virginia D. Schmithb, John E. Dillbergerb, Rodney L. Pagea,c

a North Carolina State University, College of Veterinary Medicine, Raleigh, North Carolina, USA;
b Bioanalysis and Drug Metabolism, Clinical Pharmacology, Medicine Safety Evaluation Departments, Glaxo Wellcome Inc., Research Triangle Park, North Carolina, USA;

Key Words. Thrombocytopenia • Thrombopoietin • Mimetic peptide • GW395058 • Canine • Pharmacokinetics • Pharmacodynamics

Marlene L. Hauck, D.V.M., Ph.D., NCSU-CVM, 4700 Hillsborough St., Raleigh, North Carolina 27606, USA. Telephone: 919-513-6272; Fax: 919-513-6336; e-mail: marlene_hauck{at}ncsu.edu


   ABSTRACT
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 Abstract
Introduction
 Methods and Materials
 Results
 Discussion
 Conclusion
 References
 
GW395058, a PEGylated peptide agonist of the thrombopoietin receptor, stimulates megakaryocytopoiesis and has previously been shown to increase platelet counts in vivo. The pharmacokinetics and pharmacodynamics of GW395058 were characterized using a randomized, crossover study in a large-animal model (dog) of chemotherapy-induced thrombocytopenia.

Nine beagle dogs received i.v. carboplatin (350 mg/m2) on day 0 and day 28. GW395058 (1.31 mg/kg) (n = 6) or vehicle control (n = 3) was administered on day 1 and day 29 either as an i.v. bolus or s.c. injection. After i.v. administration, peak concentrations of GW395058 occurred rapidly, while the half-life averaged approximately 56 h. Bioavailability (± standard deviation) of GW395058 given s.c. was 78.2% (20.9%).

GW395058 (i.v. and s.c.) ameliorated the platelet nadir (p = 0.0086) and resulted in a shorter time to recovery compared to the control group. The mean nadir platelet counts following carboplatin administration were 197,000 cells/µl (80,000) for the i.v. GW395058-dose group, 183,000 cells/µl (72,000) for the s.c.-dose group and 71,000 cells/µl (38,000) for the vehicle-alone group.

GW395058 reduced the thrombocytopenic effects of carboplatin in dogs. No GW395058-related adverse side effects were observed.


   INTRODUCTION
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 Abstract
 Introduction
Methods and Materials
 Results
 Discussion
 Conclusion
 References
 
Myelosuppression continues to be the dose-limiting toxicity of many antineoplastic agents, including carboplatin [1]. While neutropenia may be diminished with recombinant human G-CSF (rHuG-CSF), thrombocytopenia is often treated clinically by platelet transfusion. Platelet transfusions can be costly and present the risk of adverse reactions [2, 3]. Human recombinant growth factors such as interleukin 1{alpha} (IL-1{alpha}), IL-3, and IL-6, have shown limited preclinical efficacy in treatment of thrombocytopenia, but may produce fever, headache, myalgia, chills, and hypotension [4-9]. Recombinant IL-11 has been approved for the treatment of chemotherapy-induced thrombocytopenia, although its use has been associated with notable side effects [10]. Similarly, rHu thrombopoietin (rHuTPO), and PEGylated-megakaryoctye growth and development factor (PEG-rHuMGDF) are currently undergoing clinical investigation [11-15]. While rHuTPO has not been associated with notable side effects in clinical trials, evidence of TPO-neutralizing antibodies in patients participating in cancer and platelet donor clinical trials forced the discontinuation of PEG-rHuMGDF development [16].

Not long after TPO was first reported, a 28-amino acid TPO mimetic peptide (AF13948) was described that was equipotent to TPO in cell-based assays [17]. Subsequent to these studies, the sequence of AF13948 was modified with amino acid substitution and the resulting peptide dimer, AF15705, PEGylated to produce GW395058. In vitro, GW395058 stimulates the growth of HuTPO receptor-transfected BaF3 cells and is equipotent to rHuTPO in stimulating megakaryocyte colony formation [18]. In mice, GW395058 has a long plasma half-life (t1/2), elevates platelet counts, and accelerates platelet recovery in a model of chemotherapy-induced myelosuppression [19]. Recent animal studies suggest that repeated dosing with GW395058 does not induce rHuTPO-neutralizing antibodies [20, 21].

The objective of this study was to characterize the pharmacokinetics and pharmacodynamics (PK/PD) of GW395058 and assess its safety and efficacy in a large-animal model of chemotherapy-induced thrombocytopenia. The effect of GW395058, following i.v. and s.c. administration, on significant thrombocytopenia induced by carboplatin was evaluated in a crossover study in normal beagle dogs. This model was developed to closely simulate therapeutic drug administration schemes in humans.


   METHODS AND MATERIALS
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 Abstract
 Introduction
 Methods and Materials
Results
 Discussion
 Conclusion
 References
 
Animal Handling, Dosing, and Sample Collection
Nine adult beagle dogs (three male, six female) weighing 10-16 kg were evaluated with a physical examination, CBC, and serum biochemistry screen prior to study. Dogs were separated into three treatment groups (Table 1Go). The first group (n = 3) received GW395058 as a single i.v. bolus during the first course of carboplatin (day 1) and as an s.c. injection during the second course of carboplatin (day 29). The second group (n = 3) received GW395058 s.c. on day 1 and i.v. on day 29. The third group (n = 3) received vehicle (placebo) s.c. on day 1 and i.v. on day 29 (Table 1Go). Carboplatin, 350 mg/m2 in 50 ml 5% dextrose in water, was administered as a 30-min infusion through a peripherally located i.v. catheter on day 0 and day 28. This dose was selected, based on a previous dose-escalation study, to produce an approximate 80% drop from baseline platelet numbers [22]. GW395058 was administered at a dose of 1.31 mg/kg. In addition, rHuG-CSF, 5 µg/kg s.c., was administered once a day for eight days beginning 10 days after each carboplatin dose to prevent neutropenia. Enrofloxacin (28.4 mg twice a day) was given to dogs with neutropenia of less than 1,500 cells per µl of blood or at the discretion of the investigator to prevent sepsis. Dogs were evaluated daily for evidence of vomiting, diarrhea, anorexia, and depression.


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  		Table 1. Study design
 
Blood samples (4 ml) for PK evaluation of GW395058 were collected pretreatment (0) and at 0.08 (5 min), 0.25, 0.5, 1.0, 2, 4, 8, 12, 24, 48, 72, 96, 120, 144, and 168 h following the i.v. dose of GW395058 or placebo, and 0, 0.5, 1, 2, 4, 8, 12, 16, 20, 24, 30, 36, 48, 72, 96, 120, 144, 168, and 192 h following the s.c. dose of GW395058 or placebo. Blood samples were allowed to clot on ice, then centrifuged, and serum was removed for analysis. All serum samples were frozen at -20°C as soon as possible after collection and were shipped to the analytical laboratory, frozen on dry ice, and analyzed for GW395058 concentration. Blood samples (1 ml) for hematologic analysis were collected on days -7, -3, -1, 0, 2, 4, 6, 8, 10, 12, 14, 16, 18, 21, 24, 27, 28, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 50, 53, 57, 60, and 65. Parameters measured were platelet count, mean platelet volume, platelet distribution width, plateletcrit, total and differential white blood cell counts, reticulocyte count, red blood cell count, hemoglobin concentration, hematocrit, red blood cell indices (MCV, MCH, and MCHC), and red blood cell distribution width. Hematologic effects reflecting bone marrow toxicity were categorized using published toxicity grading scales for dogs similar to World Health Organization toxicity grades for humans [22]. Serum samples (1 ml) for clinical chemistry analysis were collected prior to each carboplatin dose to assess potential non-marrow toxicity. Serum chemistry analysis consisted of creatinine, blood urea nitrogen, liver enzymes, albumin, total bilirubin, serum electrolytes (Ca+2, Na+2, K+, Cl–, and HCO3–), glucose, and total globulin determinations on each dog.

Determination of GW395058 Serum Concentrations
Concentrations of GW395058-like immunoreactive material in dog serum were determined by using a modification of a previously described competitive binding radioimmunoassay (RIA) [21, 23]. In this RIA, diluted rabbit antiserum was incubated overnight at 4°C with radioligand (3H-AF15705) and aliquots of study samples or spiked (GW395058) serum calibration standards. The next day bound and free radioligand was separated by incubating for 1 h at 4°C with antirabbit immunoprecipitation reagent (Sac-Cel®; IDS Ltd.; Boldon, UK), followed by the addition of 2 ml of cold phosphate-buffered saline (pH 7.2) containing 0.1% bovine serum albumin and 0.1% Tween-20. Assay tubes were centrifuged for 10 min, and the supernatant aspirated to waste. The pellets were resuspended in 2 ml of water and decanted into 20 ml scintillation vials containing 10 ml of scintillation fluid. Bound radioligand was quantitated in a liquid scintillation counter, and calibration curves were derived by using the program, Multicalc (Wallac; Turku, Finland; http://www.wallac.com), from which control and study sample concentrations were interpolated. The limits of quantitation were 0.05-2,628 µg/ml for GW395058.

PK Calculations
Noncompartmental PK analysis [24] was performed on the serum concentration data for each subject. All PK calculations were performed using WinNonlin, Professional Network Version 1.5 (Scientific Consulting Inc.; Cary, NC). The following parameters were calculated for each dog receiving i.v. administration of GW395058: the maximum plasma concentration (Cmax), the time to Cmax (Tmax), the area under the concentration versus time curve from time zero to time infinity (AUC{infty}), the total clearance (CL), steady-state volume of distribution (Vss), and elimination t1/2. Following s.c. dosing, the Cmax, Tmax, AUC{infty}, and t1/2 were determined. In addition, bioavailability (F) was calculated by dividing the AUC{infty} for each subject following s.c. dosing by the AUC{infty} for the same subject following i.v. dosing.

The data were summarized using general descriptive statistics. A comparison (analysis of variance) of mean PD parameters was done using Tukey's Studentized Range Test in the SAS System for Windows, Release 6.12, TS Level 0020 (The SAS Institute; Cary, NC). Differences were declared statistically significant when p < 0.05.


   RESULTS
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 Abstract
 Introduction
 Methods and Materials
 Results
Discussion
 Conclusion
 References
 
Mean GW395058 concentration versus time plots following i.v. and s.c. administration are shown in Figure 1Go. Table 2Go shows the mean (± standard deviation) day 1 and day 29 PK parameter estimates following i.v. and s.c. administration of GW395058. In general, t1/2 values were long (average range: 56 h-82 h) following i.v. and s.c. administration, and CL values following i.v. dosing were low (0.73 ml/h/kg). After i.v. administration, peak concentrations of GW395058 (36.9 ± 7.0 µg/ml) occurred rapidly, while the t1/2 averaged approximately 56 h. As expected, after s.c. injection, the Cmax (8.85 ± 1.84 µg/ml) was lower (p < 0.05, compared with i.v.) and the Tmax occurred much later (median 54 h versus 0.17 h) than after i.v. dosing. The bioavailability of GW395058 when administered s.c. was high, but variable (78.2% ± 20.9%; range 42%-98%). t1/2 was more variable following s.c. dosing (82.3 h ± 34 h) than following i.v. dosing (56 h ± 8.9 h). The coefficients of variation for F and t1/2 were 55% and 45% for females and 8.5% and 17% for males, respectively.



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  		Figure 1. Mean serum concentration of GW395058 (1.31 mg/kg) following i.v. or s.c. administration.

 

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  		Table 2. PK parameters of GW395058 (1.31 mg/kg) in dogs treated with carboplatin (350 mg/m2). Data = mean (SD)
 
Mean platelet and absolute neutrophil counts as a function of time are shown in Figures 2 and 3GoGo, respectively. A platelet nadir occurred in all groups (Table 3Go), although the GW395058-treated groups experienced a significantly less severe nadir (p = 0.0086), which occurred earlier and recovered more quickly than in the control group. Platelet recovery in the GW395058-treated groups exceeded the upper limit of the normal reference range by approximately 50%. Thrombocytosis occurred within 12 days post-carboplatin and persisted until 28 days post-carboplatin. This was not observed in the placebo group. Neutrophil nadirs (Table 3Go) were not significantly different between treatment groups (p = 0.0783); however, with a larger sample size this trend may prove significant. rHuG-CSF-induced neutrophilia was much greater in treated than in control dogs (Fig. 3Go). No dogs died due to hematologic toxicity. Thombocytopenia, neutropenia, and overall hematologic toxicity were graded as absent, mild, moderate, or severe (Table 4Go), with moderate or severe toxicity being defined as dose-limiting toxicity. By this definition, dose-limiting thrombocytopenia, neutropenia, or overall hematologic toxicity were less frequent in treated dogs than in controls. No abnormalities were detected in the serum chemistry profiles of any dogs.



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  		Figure 2. Mean platelet counts in dogs following carboplatin (350 mg/m2 i.v.) and i.v. or s.c. administration of GW395058 (1.31 mg/kg). A= carboplatin dose; B = GW395058 dose.

 


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  		Figure 3. Mean absolute neutrophil counts in dogs following carboplatin (350 mg/m2 i.v.) and i.v. or s.c. administration of GW395058 (1.31 mg/kg). A= carboplatin dose; B = GW395058 dose.

 

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  		Table 3. Nadir platelet and neutrophil values (x 1,000 cells/µl) in dogs treated with carboplatin (350 mg/m2 i.v.) and GW39505
 

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  		Table 4. Distribution of hematologic toxicity in dogs treated with carboplatin (350 mg/m2) and GW395058
 
There were six incidents of vomiting, five on treatment day 1 and one on treatment day 29. Vomiting occurred within eight hours of GW395058 or placebo administration. Since these events were equally distributed across groups with two events per treatment group, and since vomiting may be associated with carboplatin administration, it is unlikely that they are related to GW395058.


   DISCUSSION
Top
 Abstract
 Introduction
 Methods and Materials
 Results
 Discussion
Conclusion
 References
 
A PK/PD study of GW395058 in dogs showed that GW395058 could ameliorate the platelet nadir in a dog model of chemotherapy-induced thrombocytopenia. This study also is the first to fully characterize the PK of GW395058 after s.c. and i.v. administration in dogs. The implications of results from this study are discussed below.

Thrombocytopenia can be achieved routinely and safely in normal dogs using carboplatin. Carboplatin, 350 mg/m2 i.v., produces a drop in platelets of approximately 80% from baseline, providing a valuable canine model of significant thrombocytopenia. Carboplatin-induced hematologic toxicity was obtained with minimal gastrointestinal toxicity.

GW395058 administration resulted in improvement of hematologic toxicity following chemotherapy in both the i.v. and s.c.-dose groups. The treated groups had a higher platelet nadir, a shorter time to recovery and a rebound thrombocytosis compared to the placebo group. The level of dose-limiting toxicity (Table 4Go) for the control group following multiple courses of carboplatin was similar to that observed in the phase I carboplatin study by Page et al. [22]. However, direct comparisons of toxicity are not possible due to the administration of rHuG-CSF in this study.

GW395058 has many interesting PK features. First, GW395058 has a low CL and a limited volume of distribution (Note: the Vss was approximately equal to plasma volume). In addition, the t1/2 was long following i.v. administration of GW395058. These findings are consistent with the fact that the compound is a PEGylated peptide. It is also important to note that GW395058 is adequately absorbed following s.c. administration. As expected, the Cmax was lower and the Tmax was later with s.c. dosing. Although not statistically significantly different, the increase in t1/2 after s.c. dosing versus i.v. dosing and the long tmax suggest that the absorption of GW395058 may be slower than the elimination rate, and that the observed terminal elimination t1/2 may be an estimate of the absorption rate, as has been previously described for other compounds following extravascular administration [24]. Day 1 and day 29 PK parameter estimates were not significantly different.


   CONCLUSION
Top
 Abstract
 Introduction
 Methods and Materials
 Results
 Discussion
 Conclusion
References
 
No clinical or hematologic evidence of toxicity was detected relative to GW395058 administration. GW395058 reduces the thrombocytopenic effects of carboplatin in dogs. Further studies are needed to define the role of GW395058 in the management of chemotherapy-induced thrombocytopenia and to determine other potential applications of GW395058.


   ACKNOWLEDGMENTS
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 Abstract
 Introduction
 Methods and Materials
 Results
 Discussion
 Conclusion
 References
 
This work was supported entirely by Glaxo Wellcome Inc., Research Triangle Park, NC 27709.

The authors gratefully acknowledge Sile Huyan, Maureen Trogdon, Debbie Little, and Anne Myers for their outstanding technical assistance.


   FOOTNOTES
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 Abstract
 Introduction
 Methods and Materials
 Results
 Discussion
 Conclusion
 References
 
c Current address: Cornell University, College of Veterinary Medicine, Ithaca, New York, USA Back


   References
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 Abstract
 Introduction
 Methods and Materials
 Results
 Discussion
 Conclusion
 References
 

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Received June 27, 2000; accepted for publication June 27, 2000.



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