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1.
Int J Toxicol ; 30(4): 385-404, 2011 Aug.
Article in English | MEDLINE | ID: mdl-21832269

ABSTRACT

RWJ-800088 is a novel, potent polyethylene glycol (PEG)-conjugated thrombopoietin (TPO) mimetic that increases platelet levels and protects against thrombocytopenia. A nonclinical safety program was customized for this peptide that takes into account its protein-like structure, synthetic chemical nature, agonist pharmacologic activity, and mode of administration. In repeat-dose toxicity studies, the salient findings were dose-related increases in circulating platelet counts, mean platelet volume, and megakaryocytes in the bone marrow with no antibody formation. Reversible myelofibrosis and hyperostosis were observed in rats, but not dogs, when the circulating platelet levels exceeded 3× those of vehicle controls. The bone effects were due to the exaggerated pharmacologic effect and excessive stimulation and elevation of megakaryocytes by TPO, which results in intramedullary proliferation of fibroblasts and mesenchymal cells followed by osseous metaplasia. These findings support the use of platelet elevations of >3× as a stopping criterion to prevent potential adverse bone-related effects in humans.


Subject(s)
Blood Platelets/drug effects , Drug Evaluation, Preclinical/methods , Homeostasis/drug effects , Peptides/pharmacokinetics , Animals , Blood Platelets/cytology , Bone Marrow/metabolism , Bone Marrow/pathology , Dogs , Dose-Response Relationship, Drug , Female , Guinea Pigs , Humans , Hyperostosis/pathology , Intercellular Signaling Peptides and Proteins , Male , Megakaryocytes/drug effects , Peptides/immunology , Peptides/toxicity , Primary Myelofibrosis/pathology , Rabbits , Rats , Thrombocytopenia/drug therapy , Toxicity Tests
2.
Toxicol Pathol ; 39(2): 337-47, 2011 Feb.
Article in English | MEDLINE | ID: mdl-21422260

ABSTRACT

In a three-week oral gavage toxicity study in rats, a high incidence of respiratory symptoms and high mortality was noted in compound-dosed rats only. Because of audible respiration, an effect in the upper respiratory tract was suspected and the nasal cavity was included for examination. Histology revealed extensive necrosis and purulent inflammation within the nasal passages, indicative of direct irritation. Since posterior nasal regions were most affected, with food material present within the inflammatory exudates, reflux and retrograde aspiration of irritant material (possibly stomach contents with test formulation) into the nasal cavity were suspected. Lowering the dose volume and fasting the rats prior to gavage dosing substantially reduced the respiratory effects and mortality. The current article focuses on the histological changes in the nasal cavity indicative of gavage-related reflux and provides guidance on differentiation between technical gavage error and gavage-related reflux.


Subject(s)
Dyspnea/pathology , Enteral Nutrition/adverse effects , Gastroesophageal Reflux/pathology , Nasal Cavity/pathology , Administration, Oral , Animals , Dose-Response Relationship, Drug , Gastric Emptying , Gastroesophageal Reflux/metabolism , Male , Organ Size , Rats , Rats, Sprague-Dawley , Toxicity Tests
3.
Toxicol Pathol ; 39(2): 348-60, 2011 Feb.
Article in English | MEDLINE | ID: mdl-21422261

ABSTRACT

After oral gavage dosing of rats, reflux may occur, resulting in serious respiratory effects and mortality. Published information on gavage-related reflux is limited, as it has not yet been a focus of research. Nevertheless, it represents a recurrent challenge in daily toxicology practice of oral gavage dosing. The absence of clear guidance and criteria for the identification and management of reflux-induced effects can limit the ability to properly interpret toxicity study results. The review presented herein includes an overview of experimental data from gavage studies in rats, in which reflux was observed, and provides a comprehensive analysis of the literature on reflux in general and the different potential pathways contributing to gavage-related reflux in rats. The article aims to increase the awareness and understanding of the pathogenesis of gavage-related reflux and provides guidance on identification of potential risk factors, as well as interpretation of histological changes and their toxicological relevance. Furthermore, differentiation of reflux-induced effects from direct compound-related toxicity and from gavage errors is addressed in particular, and the importance of nasal histology is discussed.


Subject(s)
Enteral Nutrition/adverse effects , Gastroesophageal Reflux/pathology , Nasal Cavity/pathology , Administration, Oral , Animals , Dyspnea , Gastric Acid/metabolism , Gastric Emptying , Gastroesophageal Reflux/metabolism , Rats , Risk Factors
4.
Cancer Chemother Pharmacol ; 66(6): 1173-84, 2010 Nov.
Article in English | MEDLINE | ID: mdl-20661737

ABSTRACT

PURPOSE: To examine whether a conventional bioequivalence approach is sufficient to ensure the therapeutic equivalence of liposomal products, the pharmacokinetics, efficacy and toxicity of different formulation variants of the marketed Doxil(/Caelyx product, pegylated liposomal doxorubicin (PLD), were evaluated in several preclinical models. METHODS: Six different variants of the marketed PLD formulation were prepared by incorporating minor changes in the composition and liposome size of the original formulation. The pharmacokinetics of 5 formulations were evaluated in albino mice following i.v. administration at 6 mg/kg. Selected variants along with Doxil/Caelyx (formulation 1, Doxil-control) were tested for antitumor activity in the MDA-MB-231 xenograft mouse model following 3 repeated administrations at 2 mg/kg or 3 mg/kg (once weekly for 3 weeks) and/or toxicity in Cynomolgus monkeys following 6 repeated administrations at 2.5 or 4.0 mg/kg. Formulations 1-4 were tested for antitumor activity and formulations 1, 2, 6 and 7 were evaluated in a monkey toxicity study. The toxicokinetics of total doxorubicin was determined after the first and last dose in the monkey toxicity study. RESULTS: In the albino mouse, formulations 2 and 3 had plasma pharmacokinetic profiles similar to Doxil-control (formulation 1). Although these three formulations had similar pharmacokinetic profiles, formulation 2 showed significantly (P < 0.05) longer survival time and better efficacy (reduced tumor volume) over other formulations tested for antitumor activity at the 3 mg/kg dose. In monkeys, formulation 2 gave systemic exposure of doxorubicin approximately the same as formulation 1; however, multi-focal degeneration of renal cortical tubules and hypocellularity of the bone marrow were observed with formulation 2 but not with formulation 1 (Doxil-control). Formulations 6 and 7 gave lower exposure to doxorubicin compared to Doxil-control, but were associated with higher severity and frequency of toxic effects (hematological effects, elevated liver enzymes). It was concluded that plasma pharmacokinetics and systemic exposure of doxorubicin did not correlate well with the antitumor activity and toxicity profiles for PLD products. Hence, a conventional bioequivalence approach is not appropriate for establishing therapeutic equivalence of generic PLD products. A carefully designed clinical study evaluating clinical safety, efficacy and pharmacokinetics should be considered for establishing the therapeutic equivalency of generic versions of Doxil.


Subject(s)
Antineoplastic Agents/pharmacology , Breast Neoplasms/drug therapy , Doxorubicin/analogs & derivatives , Polyethylene Glycols/pharmacology , Animals , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/blood , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/toxicity , Area Under Curve , Chemistry, Pharmaceutical , Disease Models, Animal , Doxorubicin/administration & dosage , Doxorubicin/blood , Doxorubicin/pharmacokinetics , Doxorubicin/pharmacology , Doxorubicin/toxicity , Drug Administration Schedule , Female , Heart/drug effects , Humans , Macaca fascicularis , Mice , Mice, Nude , Polyethylene Glycols/administration & dosage , Polyethylene Glycols/pharmacokinetics , Polyethylene Glycols/toxicity , Survival Analysis , Therapeutic Equivalency , Transplantation, Heterologous , Treatment Outcome
5.
J Clin Pharmacol ; 50(4): 380-91, 2010 Apr.
Article in English | MEDLINE | ID: mdl-20097935

ABSTRACT

The FDA guidance on exploratory IND studies is intended to enable sponsors to move ahead more efficiently with the development of promising candidates. A survey of PhRMA member companies was conducted in 2007 to obtain a cross-sectional industry perspective on the current and future utility of exploratory IND studies. About 56% of survey responders (9 companies of 16 survey responders) conducted or were planning to conduct clinical studies under exploratory INDs. The majority of microdosing studies are performed to characterize human pharmacokinetics or to examine target organ pharmacokinetics using PET imaging techniques. On the other hand, the majority of pharmacological end point studies conducted under exploratory IND are performed to determine whether the compound modulated its pharmacological target or to evaluate the degree of saturation of a target receptor. The present survey suggests that although the merits of exploratory INDs are still being debated, the diversity in the applications cited, the potential for early clinical guidance in decision making and the increasing pressure on containing drug development costs, suggest that the exploratory IND/CTA will be a valuable option with evolving and possibly more specific applications for the future.


Subject(s)
Clinical Trials as Topic/methods , Drug Industry/methods , Drugs, Investigational , Investigational New Drug Application , Cross-Sectional Studies , Drug Discovery/methods , Drugs, Investigational/pharmacokinetics , Drugs, Investigational/therapeutic use , Humans , United States , United States Food and Drug Administration
7.
AAPS J ; 9(3): E284-97, 2007 Jul 20.
Article in English | MEDLINE | ID: mdl-17915830

ABSTRACT

Application of "omics" technology during drug discovery and development is rapidly evolving. This review evaluates the current status and future role of "metabonomics" as a tool in the drug development process to reduce the safety-related attrition rates and bridge the gaps between preclinical and clinical, and clinical and market. Particularly, the review looks at the knowledge gap between the pharmaceutical industry and pediatric hospitals, where metabonomics has been successfully applied to screen and treat newborn babies with inborn errors of metabolism. An attempt has been made to relate the clinical pathology associated with inborn errors of metabolism with those of drug-induced pathology. It is proposed that extending the metabonomic biomarkers used in pediatric hospitals, as "advanced clinical chemistry" for preclinical and clinical drug development, is immediately warranted for better safety assessment of drug candidates. The latest advances in mass spectrometry and nuclear magnetic resonance (NMR) spectroscopy should help replace the traditional approaches of laboratory clinical chemistry and move the safety evaluation of drug candidates into the new millennium.


Subject(s)
Biomarkers , Drug-Related Side Effects and Adverse Reactions , Metabolism, Inborn Errors/drug therapy , Metabolism/physiology , Enzymes/deficiency , Humans , Metabolism, Inborn Errors/enzymology
8.
Br J Clin Pharmacol ; 54(5): 478-84, 2002 Nov.
Article in English | MEDLINE | ID: mdl-12445026

ABSTRACT

AIMS: To assess the pharmacokinetic and pharmacodynamic profile of the novel PDE4 inhibitor V11294A (3-(3-cyclopentyloxy-4-methoxybenzyl)-6-ethylamino-8-isopropyl-3H purine hydrochloride) in healthy male volunteers. METHODS: This was a double-blind, single dose, randomized crossover study in eight healthy volunteers who received a single oral, fasting dose of V11294A (300 mg) or placebo. Blood samples were taken before and 0.5, 1, 2, 2.5, 3, 4, 6, 9, 12, 18 and 24 h after oral dosing for determination of plasma concentrations of V11294A. Blood samples were also taken before and 3 and 24 h after dosing for the assessment of the effect of V11294A on mononuclear cell proliferation and tumour necrosis factor (TNF) release in whole blood. RESULTS: Following a single oral dose of 300 mg V11294A, plasma concentrations of V11294A and its active metabolite V10332 reached Cmax (ng ml-1; mean +/- s.d.; 1398 +/- 298, 1000 +/- 400, respectively) after 2.63 +/- 0.79 and 5.9 +/- 2.3 h, respectively. For V11294A and V10332, t1/2 were 9.7 +/- 3.9 and 9.5 +/- 1.7 h, and AUC(0, infinity ) were 18100 +/- 6100 and 18600 +/- 8500 ng ml-1 h, respectively. At 3 h dosing, plasma concentrations of V11294A and V10332 (3-(3-cyclopentyloxy-4-methoxy-benzyl)-8-isopropyl-3H-purin-6-ylamine) were 1300 +/- 330 and 860 +/- 300 ng ml-1, 7 and 3 times their in vitro IC50s for inhibition of TNF release and proliferation, respectively. Treatment with V11294A resulted in a significant reduction of lipopolysaccharide (LPS)-induced TNF release at 3 h (P < 0.001) and at 24 h (P < 0.05) post ingestion. The amount of TNF released (pmol ml-1) in response to a submaximal concentration of LPS (4 ng ml-1) was not significantly altered following placebo treatment (before 681 +/- 68 vs 3 h postdose 773 +/- 109, P = 0.27). In contrast, there was a significant reduction in the amount of TNF released following treatment with V11294A (before 778 +/- 87 vs 3 h postdose 566 +/- 72, P = 0.02). Phytohaemagluttinin (PHA) stimulated the incorporation of [3H]-thymidine in whole blood prior to drug administration. V11294A inhibited the PHA-induced proliferation at 3 h (P < 0.05). No adverse reactions were noted following single oral administration of V11294A. CONCLUSIONS: A single oral 300 mg dose of V11294A administered to healthy volunteers results in plasma concentrations adequate to inhibit activation of inflammatory cells ex vivo, which persists for at least 24 h without any adverse reactions.


Subject(s)
3',5'-Cyclic-AMP Phosphodiesterases/antagonists & inhibitors , Phosphodiesterase Inhibitors/pharmacokinetics , Purines/pharmacokinetics , Administration, Oral , Adult , Cell Division , Cross-Over Studies , Cyclic Nucleotide Phosphodiesterases, Type 4 , Dose-Response Relationship, Drug , Double-Blind Method , Half-Life , Humans , Male , Middle Aged , Monocytes/drug effects , Monocytes/metabolism , Phosphodiesterase Inhibitors/administration & dosage , Phosphodiesterase Inhibitors/pharmacology , Purines/administration & dosage , Purines/pharmacology , Tumor Necrosis Factor-alpha/antagonists & inhibitors
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