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Clinical pharmacology of recombinant human follicle-stimulating hormone. II. Single doses and steady state pharmacokinetics.

Abstract：

OBJECTIVE:To assess the single-dose pharmacokinetics of a recombinant human FSH preparation (Gonal-F; Laboratoires Serono, Aubonne, Switzerland), administered by i.v., IM, and SC routes and its pharmacokinetics at steady state after multiple dosing by the SC route. DESIGN:Twelve healthy down-regulated female volunteers received in random order three single doses of recombinant human FSH (150 IU, i.v., IM, and SC), with each administration separated by 1 week. The volunteers then received multiple recombinant human FSH doses by the SC route (150 IU one time per day) for 7 days. Follicle-stimulating hormone concentrations were measured by an immunoradiometric assay and an in vitro granulosa cell aromatase bioassay. RESULTS:After a single administration, the pharmacokinetics of recombinant human FSH were well-described by a two-compartment model after i.v. administration and by a one-compartment model with first order absorption after IM or SC administration. The mean total clearance of FSH was approximately 0.6 L/h, and renal clearance accounted for one tenth of the total elimination after i.v. administration. The distribution half-life was close to 2 hours. The terminal half-life was nearly 1 day when estimated either by modeling the i.v. data set or from analysis of the terminal phase of the steady state pharmacokinetic curve or from the time taken to reach steady state after repeated SC administrations. After single IM and SC injection, two thirds of the administered dose was available systemically. The cumulation factor for repeated SC administration was approximately 3 when steady state was reached. The in vitro bioassay data confirmed these estimations. The temporal evolution of the bioassay:immunoassay ratio suggests either metabolic selection or activation of recombinant human FSH toward forms with greater in vitro bioactivity. CONCLUSION:The estimation of the elimination half-life of approximately 1 day indicates that the maximal effect of a given dose of recombinant human FSH administered daily cannot be observed until 3 to 4 days of repeated administration. This indicates that, on a pure pharmacokinetic basis, physicians should wait at least 4 days to assess the efficacy of a given dose of recombinant human FSH and that they should not modify dosage too frequently.

journal_name

Fertil Steril

journal_title

Fertility and sterility

authors

le Contonnec JY,Porchet HC,Beltrami V,Khan A,Toon S,Rowland M

subject

Has Abstract

pub_date

1994-04-01 00:00:00

pages

679-86

issue

eissn

0015-0282

issn

1556-5653

pii

S0015-0282(16)56645-X

journal_volume

pub_type

临床试验,杂志文章,随机对照试验

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Clinical pharmacology of recombinant human follicle-stimulating hormone. II. Single doses and steady state pharmacokinetics.