Treatment of unruptured tubal pregnancy with methotrexate: pharmacokinetic analysis of local versus intramuscular administration.
OBJECTIVE
To determine the optimal dose and route of methotrexate (MTX) in the treatment of ectopic pregnancy (EP).


METHODS
Prospective randomized study.


METHODS
Department of Obstetrics and Gynecology (A. Béclère Public Hospital, Clamart, France, Paris-Sud University).


METHODS
Forty-eight patients with unruptured EP clearly visualized by ultrasound were randomly allocated into four groups of treatment (12 patients in each group): group 1, 1 mg/kg injected locally in the ectopic gestational sac and 1 mg/kg by IM administration 48 hours later; group 2, 1 mg/kg locally; group 3, 0.5 mg/kg locally; group 4, 1 mg/kg by IM administration. Inclusion criteria used a pretherapeutic score < or = 12. Blood samples were collected at time 0.25, 0.5, 1, 2, 6, 12, 24, 36, and 48 hours after MTX administration. Pharmacokinetics of MTX plasma levels were measured by fluorescence polarization immunoassay. Kinetic parameters were compared by Wilcoxon test and Mann-Whitney test. Plasma hCG concentrations were assessed on days 2, 5, and 10 and then weekly until they returned to undetectable levels.


RESULTS
Success rate was 12 of 12, 11 of 12, 10 of 12, and 10 of 12 in groups 1, 2, 3, and 4, respectively. Six patients in group 3 required an additional MTX IM injection because of an inadequate decrease of hCG plasma levels. Five patients underwent surgery for abdominal pain or inadequate decrease of hCG. Area under the curve decreased more rapidly after injection in the gestational sac alone than after IM injection and was similar in groups 1 and 2 after local injection and lower in group 3. Terminal half-life and mean residence time remained similar in the four groups. Systemic side effects of MTX therapy occurred in three cases in groups 1 and 4. The regression curve of hCG plasma levels appeared similar in the four groups with a decrease to pretreatment values between days 6 and 8 after an initial rise after MTX was given.


CONCLUSIONS
Area under the curve found after injection in the ectopic sac may be related to a decrease in bioavailability of MTX that links to trophoblastic cells. Patients in group 3 were clearly undertreated by 0.5 mg/kg MTX and required additional therapy. Residual values of MTX plasma levels were always below the limit of detection of our assay and confirmed that citrovarum factor rescue is unnecessary. Injection of 1 mg/kg of MTX in the ectopic sac appears as effective as systemic (IM) injection with less side effects for the patients.
Fernandez
H
H
Department of Obstetrics and Gynecology, A. Béclère Hospital, Clamart, France.
Bourget
P
P
Ville
Y
Y
Lelaidier
C
C
Frydman
R
R
D006063:Chorionic Gonadotropin / Q000097:blood; D005321:Extraembryonic Membranes / Q000187:drug effects; D005260:Female; D005454:Fluorescence Polarization; D006207:Half-Life; D006801:Humans; D007273:Injections, Intramuscular; D008727:Methotrexate / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D011247:Pregnancy; D011274:Pregnancy, Tubal / Q000188:drug therapy*; D011446:Prospective Studies
D006063:Chorionic Gonadotropin; D008727:Methotrexate