Teratology Studies

Safety assessment studies of pharmaceuticals have typically involved administration of the test compound during the embryonic period, when the organ systems form, which encompasses GD 20 to 50 in the commonly used species, the rhesus and cynomolgus macaques. With the emergence of biopharmaceuticals, the safety assessment protocols have been altered to provide for longer exposure of the con-ceptus to include a significant portion of the fetal period. This period is characterized by rapid growth of the fetus and differentiation of organ systems, including the fetal immune system. The fetal period in the macaque extends from GD 50 to term (GD 155 and 165 in the cynomolgus and rhesus, respectively). Many protocols now include administration of the test compound until GD 70 to 100 (Figure 7.7). Future protocols involving immunomodulatory agents will probably include exposure throughout pregnancy (i.e., GD 20 to term); in certain cases, exposure may include the early postnatal period (i.e., birth to postnatal day 30).

Protocols in the near future may also require exposure from the time of conception or implantation to adequately cover early differentiation of the thymus and other components of the fetal immune system. Exposure from the time of conception will

Figure 7.7 The standard protocol for a teratology study in nonhuman primates includes exposure to a test agent during the major period of organ formation (GD 20-50) following pregnancy confirmation at GD 18 to 20. In the case of immunomodulatory agents, the test agent would be administered for a longer period (until GD 70 or 100) to cover growth and differentiation of the fetal immune system. Future protocols could extend the period of treatment to include earlier (before GD 20) or later (until term or during the postnatal period) exposure to an immunomodu-latory drug. (Hendrickx AG et al. Hum Exp Toxicol 19:1-7, 2000. With permission.)

Figure 7.7 The standard protocol for a teratology study in nonhuman primates includes exposure to a test agent during the major period of organ formation (GD 20-50) following pregnancy confirmation at GD 18 to 20. In the case of immunomodulatory agents, the test agent would be administered for a longer period (until GD 70 or 100) to cover growth and differentiation of the fetal immune system. Future protocols could extend the period of treatment to include earlier (before GD 20) or later (until term or during the postnatal period) exposure to an immunomodu-latory drug. (Hendrickx AG et al. Hum Exp Toxicol 19:1-7, 2000. With permission.)

require administration of the test compound to approximately four times more females due to the average conception per mating success of about 25%. With the current availability of ultrasound technology confirmation of pregnancy is not feasible until 3 to 4 days after implantation (i.e., 2 to 4 days after embryo attachment in the macaque, approximately GD 13 to 14) (Guo et al. 1999).

In addition to standard fetal weights and measurements, useful endpoints to measure possible adverse effects on the developing immune system include proportions of T and B lymphocytes, as well as presence and numbers of antigen-presenting cells, and the cells secreting immunoglobulins and cytokines.

Was this article helpful?

0 0
How To Bolster Your Immune System

How To Bolster Your Immune System

All Natural Immune Boosters Proven To Fight Infection, Disease And More. Discover A Natural, Safe Effective Way To Boost Your Immune System Using Ingredients From Your Kitchen Cupboard. The only common sense, no holds barred guide to hit the market today no gimmicks, no pills, just old fashioned common sense remedies to cure colds, influenza, viral infections and more.

Get My Free Audio Book


Post a comment