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Extractables and leachables are product-related impurities that result from product contact with components such as gaskets, stoppers, storage bags, cartridges, and prefilled syringes that are used for processing, storage, and/or delivery of biopharmaceuticals. These impurities are a concern for patients due to potential effects on product quality and safety. It is possible that such an impurity could directly impact the patient or indirectly impact the patient by interacting with the protein therapeutics and forming protein adducts. Adducts and leachables may or may not be detected as product-related impurities in routine stability indicating assays depending on the rigor of the analytical program. The need for the development of a thorough and holistic extractable and leachable program based on risk assessment, review of existing literature, and consolidation of industry best practices is discussed. Standardizing component use within an organization enables streamlining of the extractable-leachable program. Our strategy for an extractable-leachable program is divided into different stages, each stage detailing the activities and the department within the organization that is responsible for execution of these activities. The roles and responsibilities of the key stakeholders are identified. The integration of analytical activities with health-based risk-assessment information into the design of an extractable-leachable program is highlighted.

Trastuzumab emtansine (T-DM1) is the first antibody-drug conjugate (ADC) approved for patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer. The therapeutic premise of ADCs is based on the hypothesis that targeted delivery of potent cytotoxic drugs to tumors will provide better tolerability and efficacy compared with non-targeted delivery, where poor tolerability can limit efficacious doses. Here, we present results from preclinical studies characterizing the toxicity profile of T-DM1, including limited assessment of unconjugated DM1. T-DM1 binds primate ErbB2 and human HER2 but not the rodent homolog c-neu. Therefore, antigen-dependent and non-antigen-dependent toxicity was evaluated in monkeys and rats, respectively, in both single- and repeat-dose studies; toxicity of DM1 was assessed in rats only. T-DM1 was well tolerated at doses up to 40 mg/kg (~4400 μg DM1/m(2)) and 30 mg/kg (~ 6000 μg DM1/m(2)) in rats and monkeys, respectively. In contrast, DM1 was only tolerated up to 0.2mg/kg (1600 μg DM1/m(2)). This suggests that at least two-fold higher doses of the cytotoxic agent are tolerated in T-DM1, supporting the premise of ADCs to improve the therapeutic index. In addition, T-DM1 and DM1 safety profiles were similar and consistent with the mechanism of action of DM1 (i.e., microtubule disruption). Findings included hepatic, bone marrow/hematologic (primarily platelet), lymphoid organ, and neuronal toxicities, and increased numbers of cells of epithelial and phagocytic origin in metaphase arrest. These adverse effects did not worsen with chronic dosing in monkeys and are consistent with those reported in T-DM1-treated patients to date.

s Recombinant DNA technology enables the manufacture of proteins and antibodies with a defined specificity and uniformity, which is a vast improvement over previous methods of production by extraction and purification from human or animal blood and tissues. This chapter introduces the various classes of therapeutics that are produced using recombinant DNA technology, and provides background on the history and evolution of therapeutic hormones, enzymes, cytokines, and monoclonal antibodies from an early understanding of their value in the treatment of disease to present day production of genetically engineered human proteins and novel constructs designed to improve uniformity, safety, efficacy, or duration of effect. While this customization bears some resemblance to optimization of chemical scaffolds during lead optimization of low molecular weight chemical compounds (i.e. small molecules), there are unique considerations for the nonclinical safety evaluation of biopharmaceutical drug candidates. This chapter will describe key features of biotechnology-derived molecules, how they compare to traditional chemical compounds, and the impact these features have on preclinical safety testing during their development as medicines.

Biomedical researchers continue to make significant efforts to describe considerations for clinical safety assessment of oncology products. There is a consistent approach to characterization of the preclinical safety profile that requires consideration of a number of factors. Some of these factors include clinical application, drug attributes, and material production. Keywords: oncology products; safety assessment; anti-drug antibody response; toxicology

This study characterized the pharmacokinetics (PK) and pharmacodynamics (PD) of sibrafiban (Ro 48-3657) in the presence of aspirin, heparin, and recombinant tissue-type plasminogen activator (rt-PA) in beagles. Sibrafiban is a double prodrug that undergoes bioconversion to the inactive prodrug Ro 48-3656 and to the active IIb/IIIa antagonist, Ro 44-3888, after oral administration. After oral sibrafiban, peak Ro 48-3656 plasma concentrations were observed earlier than Ro 44-3888 and were five- to sixfold higher than Ro 44-3888 peak concentrations. Administration of sibrafiban with heparin and aspirin or heparin and rt-PA did not alter sibrafiban PK. Ro 48-3656 and Ro 44-3888 PK and inhibition of platelet-aggregation profiles in groups treated with sibrafiban and heparin/aspirin or sibrafiban and heparin/rt-PA were similar to those of the group receiving sibrafiban alone. Sibrafiban resulted in >80% inhibition of adenosine diphosphate (ADP)-mediated platelet aggregation and an approximate sixfold increase in bleeding time (BT) compared with baseline measurements. The BT increase was greater in the sibrafiban, heparin, and rt-PA-treated group, during rt-PA administration, compared with the group treated with sibrafiban alone. The recovery of platelet aggregation may be slower after administration of sibrafiban with heparin and rt-PA. Sibrafiban had no effect on rt-PA PK or heparin PD.

The effect of heparin, aspirin, and recombinat tissue-type plasminogen activator (rt-PA) on TP-9201 pharmacokinetics and pharmacodynamics was investigated in beagles. Animals received TP-9201, an Arginine-Glycine-Aspartic acid (RGD)-containing synthetic peptide glycoprotein (gp)IIbIIIa antagonist as a bolus of 0.31 mg/kg, followed by a 4-h infusion of 0.5 mg/kg/h. rt-PA was administered as a modification of the weight-adjusted standard regimen. Heparin was administered as a bolus followed by an infusion producing a 1.5- to 2-fold increase in the activated prothromboplastin time (aPTT) above baseline values. Aspirin was administered orally, approximately 24 and 2 h before TP-9201. TP-9201 had a plasma clearance of 9.9 +/- 2 ml/min/kg and a volume of distribution that was larger than plasma volume. Administration of heparin and aspirin with TP-9201 did not affect the clearance of TP-9201, whereas rt-PA resulted in a faster clearance (p = 0.05). Whether the faster clearance is physiologic or a result of rt-PA interference in the TP-9201 assay is unclear. TP-9201 completely inhibited ADP-mediated platelet aggregation. After discontinuation of TP-9201, recovery of platelet aggregation had a half life (t1/2) of 2-3 h and was complete < or = 24 h. Coadministration of heparin did not interfere with TP-9201 pharmacodynamics, whereas aspirin and rt-PA slowed the recovery of platelet aggregation. The template bleeding time profile for the TP-9201-treated animals was similar to that of the aspirin-treated animals.

Nature Reviews Immunology 31 Aug 2012 (doi:10.1038/nri3192-c1) On page 2 of the original Correspondence article, under the subheading “Failure to reconcile discordant preclinical data”, the dose of 5.11A1 administered to HIS mice in the study by Legrand et al. was incorrectly stated as 0.3 mg per kg, when it should have been 0.

Background There is little guidance regarding the risk of exposure of pregnant women/ women of childbearing potential to genotoxic or teratogenic compounds via vaginal dose delivered through seminal fluid during sexual intercourse. Method We summarize current thinking and provide clinical trial considerations for a consistent approach to contraception for males exposed to genotoxic and/or teratogenic compounds or to compounds of unknown teratogenicity, and for collection of pregnancy data from their female partners. Results Where toxicity testing demonstrates genotoxic potential, condom use is required during exposure and for 5 terminal plasma half-lives plus 74 days (one human spermatogenesis cycle) to avoid conception. For non-genotoxic small molecules and immunoglobulins with unknown teratogenic potential or without a no observed adverse effect level (NOAEL) from embryo-fetal development (EFD) studies and no minimal anticipated biological effect level (MABEL), condom use is recommended for males with pregnant partner/female partner of childbearing potential. For teratogenic small molecules with estimated seminal fluid concentration and a margin between projected maternal area under the curve (AUC) and NOAEL AUC from EFD studies of ≥300 (≥100 for immunoglobulins) or in the absence of a NOAEL with a margin between MABEL plasma concentration and maternal Cmax of ≥300 (≥10 for immunoglobulins), condom use is not required. However, condom use is required for margins below the thresholds previously indicated. For small molecules with available seminal fluid concentrations, condom use is required if margins are Pregnancy data should be proactively collected if pregnancy occurs during the condom use period required for males exposed to first-in-class molecules or to molecules with a target/class shown to be teratogenic, embryotoxic or fetotoxic in human or preclinical experiments. Conclusion These recommendations, based on a precaution principle, provide a consistent approach for minimizing the risk of embryo-fetal exposure to potentially harmful drugs during pregnancy of female partners of males in clinical trials. Proactive targeted collection of pregnancy information from female partners should help determine the teratogenic potential of a drug and minimize background noise and ethical/logistical issues.