Product case study Ovitrelle

Ovitrelle (tradename in EU, sold as Ovidrel in the USA and also known as choriogonadotropin alfa) is a recombinant hCG approved for general medical use in the EU and USA in 2001. It is indicated for the treatment of female infertility due to anovulation and for patients undergoing assisted reproductive technology. It is used to trigger final follicle maturation and luteinization after follicle stimulation.

The glycoprotein hormone, consisting of an a- and a P-subunit, displays an identical amino acid sequence and very similar glycosylation detail when compared with native hCG. It is produced in an engineered CHO cell line and, after cell culture, the product is purified from the media by multistep chromatography, ultrafiltration and nanofiltration. The final product also contains mannitol, methionine, poloxamer188 sodium hydroxide and ortho-phosphoric acid and is presented in either vials or pre-filled syringes. The product is administered subcutane-ously. Following s.c. administration, maximum serum concentration is usually witnessed after 12-24 h and the product is eliminated with a mean terminal half-life of approximately 29 h. Absolute bioavailability is of the order of 40 per cent.

Pivotal pre-approval safety and efficacy was assessed in a randomized, open label, multicentre study of infertile females undergoing in vitro fertilization and embryo transfer. The primary efficacy parameter was the mean number of oocytes retrieved, which (at 13.6) was similar to the number retrieved when urinary-derived hCG was used. Serious potential side effects can include ovarian over/hyper-stimulation, sometimes with pulmonary or vascular complications. The product is marketed by Serono Inc.

recovered from the animal (either surgically or, more usually, non-surgically), and are often maintained in cell culture for a short period of time. A single embryo is then usually reimplanted into the donor female, while the remaining embryos are implanted into other recipient animals, who act as surrogate mothers, carrying the offspring to term.

This technology is most often applied to valuable animals (e.g. prize winning horses, or high milk-yield dairy cattle) in order to boost their effective reproductive capacity several-fold. All the offspring will inherit its genetic complement from the biological mother (and father), irrespective of what recipient animal carries it to term.

Gonadotrophins usually utilized to induce a superovulatory response include porcine FSH (p-FSH), porcine LH (p-LH) and PMSG. p-FSH is extracted from the pituitary glands of slaughterhouse pigs. The crude pituitary extract is usually subject to a precipitation step, using either ethanol or salts. The FSH-containing precipitate is normally subjected to at least one subsequent chromatographic step. The final product often contains some LH and low levels of additional pituitary-derived proteins.

p-LH is obtained, again, by its partial purification from the pituitary glands of slaughterhouse pigs. Although the target recipients are almost always cattle or horses, in both cases a porcine source is utilized. The use of a product derived from a species other than the intended recipient species is encouraged as it helps minimize the danger of accidental transmission of disease via infected source material (many pathogens are species specific).

ADDITIONAL RECOMBINANT HORMONES NOW APPROVED

Most superovulatory regimes utilizing p-FSH entail its administration to the recipient animal twice daily for 4-5 days. Regular injections are required due to the relatively short half-life of FSH in serum; s.c. administration helps prolong the duration of effectiveness of each injection. The 4 or 5 days of treatment with FSH is followed by a single dose of LH, promoting final follicular maturation and ovulation.

The causes of variability of superovulatory responses are complex and not fully understood. The general health of the animal, as well as its characteristic reproductive physiology, is important. The exact composition of the gonadotrophin preparations administered and the exact administration protocol also influence the outcome. The variability of FSH:LH ratios in many p-FSH preparations can affect the results obtained, with the most consistent superovulatory responses being observed when FSH preparations exhibiting low LH activity are used. The availability of recombinant FSH and LH will overcome these difficulties at least.

An alternative superovulatory regime entails administration of PMSG, which, as described earlier, exhibits both FSH and LH activity. The major rationale for utilizing PMSG is its relatively long circulatory half-life. In cattle, clearance of PMSG may take up to 5 days. The slow clearance rate appears to be due to the molecule's high content of N-acetyl-neuramic acid. This extended serum half-life means that a single dose of PMSG is sufficient to induce a superovulatory response. Paradoxically, however, its extended half-life limits its use in practice. Post-ovulatory stimulation of fol-licular growth can occur, resulting in the recovery of a reduce number of viable embryos. Attempts to negate this biological effect have centred around administration of anti-PMSG antibodies several days after PMSG administration. However, this gonadotrophin is still not widely used.

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