EAL

GDM: Pharmacologic Therapy (2008)

Citation:

Study Design:

Class:

- Click here for explanation of classification scheme.

Quality Rating:

Research Purpose:

The purpose of this study was to develop a population model of the pharmacokinetics of metformin in late pregnancy and use a partition coefficient parameter to estimate the relative fetal exposure of metformin at the time of delivery.

Inclusion Criteria:

Women who were treated with oral metformin throughout their pregnancies for NIDDM or gestational diabetes.

Exclusion Criteria:

None reported.

Description of Study Protocol:

Recruitment Women were enrolled in an ongoing clinical trial of the comparative effects of insulin and metformin in pregnancy conducted at the Queen Elizabeth Hospital and the Women's and Children's Hospital, Adelaide, South Australia.

Design 1-7 (median, 2) plasma samples per patient were obtained in the third trimester of pregnancy up until the time of delivery. A cord blood sample was obtained at the delivery of 8 of these patients, and at the delivery of another 17 patients who had been taking metformin during their pregancies but from whom no blood samples had beeen taken during pregnancy. Plasma samples were immediately frozen at -80⁰C and dispatched on dry ice to the Australian Centre for Pediatric Pharmacokinetics laboratory for metformin analysis.

Plasma metformin concentrations were measured by a validated reverse-phase HPLC method. Using first-order conditional estimation, a 2-compartment mamillary model with first-order absorption and transplacental partitioning from the gut and with the peripheral compartment representing transpartitioning to the fetus was fitted to the metformin concentration data.

Blinding used (if applicable)

Not applicable.

Intervention (if applicable)

All subjects were taking oral metformin.

Statistical Analysis

Population pharmacokinetic analysis modeling was conducted in double precision using NONMEM in conjunction with a G77 Fortran compiler.

Data Collection Summary:

Timing of Measurements

A cord blood sample was obtained at delivery and from 1-7 (median 2) plasma samples per patient were obtained in the third trimester of pregnancy until the time of delivery.

Dependent Variables

Maternal and cord plasma metformin levels at delivery

Independent Variables

Oral metformin

Control Variables

Description of Actual Data Sample:

Initial N: 27 pregnant women treated with metformin through out their pregnancies

Attrition (final N): 27 (7 NIDDM), (20 gestational diabetes)

Age: 32 years (range 26-43)

Ethnicity: unknown

Other relevant demographics:

Anthropometrics See table below

Location: Adelaide, South Australia

Maternal wt (kg)	88 (50-150)
Dose mg/day	2000 (1000-3000)
Plasma conc (mg/L)	1.2 (0.1 - 2.9)
Neonatal birth wt (kg)	3.39 (2.53-4.48)
Cord plasma conc (mg/L)	0.8 (0.1 - 2.6)

Summary of Results:

Other Findings

The typical (allometrically scaled) maternal clearance and terminal half-life in our patients (n=12) was 28 L/h/70 kg and 5.1 hours compared with 28.4 L/h and 6 hours, respectively, after a 1.5 gm oral dose to healthy patients (n=4, 72 kg mean weight), and 46.6 L/h and 5.3 hours, respectively, after a 1 gm oral dose in patients with type 2 diabetes (n=4, 82 kg mean weight).

We found no evidence that systemic clearance or half-life was any different than what was reported in non-pregnant patients.

Author Conclusion:

The pharmocokinetics of metformin in late pregnancy do not differ markedly from what has been reported previously in healthy paients and in patients iwth type 2 diabetes and do not warrant changes in prescribing metformin, at least on the basis of phamacokinetics alone. Metformin readily crosses the placenta, exposing the fetus to concentrations approaching those in the maternal circulation. The sequelae to such exposure, eg. effects on neonatal obesity and insulin resistance, remain unknown.

Funding Source:

Reviewer Comments:

Complex pharmacokinetics model to determine metformin equilibrium between fetus and mother.

Quality Criteria Checklist: Primary Research
Relevance Questions
	1.	Would implementing the studied intervention or procedure (if found successful) result in improved outcomes for the patients/clients/population group? (Not Applicable for some epidemiological studies)	Yes
	2.	Did the authors study an outcome (dependent variable) or topic that the patients/clients/population group would care about?	Yes
	3.	Is the focus of the intervention or procedure (independent variable) or topic of study a common issue of concern to dieteticspractice?	Yes
	4.	Is the intervention or procedure feasible? (NA for some epidemiological studies)	Yes

Validity Questions
1.	Was the research question clearly stated?		Yes
	1.1.	Was (were) the specific intervention(s) or procedure(s) [independent variable(s)] identified?	Yes
	1.2.	Was (were) the outcome(s) [dependent variable(s)] clearly indicated?	Yes
	1.3.	Were the target population and setting specified?	Yes
2.	Was the selection of study subjects/patients free from bias?		???
	2.1.	Were inclusion/exclusion criteria specified (e.g., risk, point in disease progression, diagnostic or prognosis criteria), and with sufficient detail and without omitting criteria critical to the study?	???
	2.2.	Were criteria applied equally to all study groups?	???
	2.3.	Were health, demographics, and other characteristics of subjects described?	???
	2.4.	Were the subjects/patients a representative sample of the relevant population?	???
3.	Were study groups comparable?		???
	3.1.	Was the method of assigning subjects/patients to groups described and unbiased? (Method of randomization identified if RCT)	???
	3.2.	Were distribution of disease status, prognostic factors, and other factors (e.g., demographics) similar across study groups at baseline?	???
	3.3.	Were concurrent controls or comparisons used? (Concurrent preferred over historical control or comparison groups.)	N/A
	3.4.	If cohort study or cross-sectional study, were groups comparable on important confounding factors and/or were preexisting differences accounted for by using appropriate adjustments in statistical analysis?	N/A
	3.5.	If case control study, were potential confounding factors comparable for cases and controls? (If case series or trial with subjects serving as own control, this criterion is not applicable.)	N/A
	3.6.	If diagnostic test, was there an independent blind comparison with an appropriate reference standard (e.g., "gold standard")?	N/A
4.	Was method of handling withdrawals described?		Yes
	4.1.	Were follow-up methods described and the same for all groups?	Yes
	4.2.	Was the number, characteristics of withdrawals (i.e., dropouts, lost to follow up, attrition rate) and/or response rate (cross-sectional studies) described for each group? (Follow up goal for a strong study is 80%.)	Yes
	4.3.	Were all enrolled subjects/patients (in the original sample) accounted for?	Yes
	4.4.	Were reasons for withdrawals similar across groups?	Yes
	4.5.	If diagnostic test, was decision to perform reference test not dependent on results of test under study?	Yes
5.	Was blinding used to prevent introduction of bias?		Yes
	5.1.	In intervention study, were subjects, clinicians/practitioners, and investigators blinded to treatment group, as appropriate?	Yes
	5.2.	Were data collectors blinded for outcomes assessment? (If outcome is measured using an objective test, such as a lab value, this criterion is assumed to be met.)	Yes
	5.3.	In cohort study or cross-sectional study, were measurements of outcomes and risk factors blinded?	N/A
	5.4.	In case control study, was case definition explicit and case ascertainment not influenced by exposure status?	N/A
	5.5.	In diagnostic study, were test results blinded to patient history and other test results?	N/A
6.	Were intervention/therapeutic regimens/exposure factor or procedure and any comparison(s) described in detail? Were interveningfactors described?		Yes
	6.1.	In RCT or other intervention trial, were protocols described for all regimens studied?	N/A
	6.2.	In observational study, were interventions, study settings, and clinicians/provider described?	N/A
	6.3.	Was the intensity and duration of the intervention or exposure factor sufficient to produce a meaningful effect?	Yes
	6.4.	Was the amount of exposure and, if relevant, subject/patient compliance measured?	???
	6.5.	Were co-interventions (e.g., ancillary treatments, other therapies) described?	Yes
	6.6.	Were extra or unplanned treatments described?	???
	6.7.	Was the information for 6.4, 6.5, and 6.6 assessed the same way for all groups?	Yes
	6.8.	In diagnostic study, were details of test administration and replication sufficient?	N/A
7.	Were outcomes clearly defined and the measurements valid and reliable?		Yes
	7.1.	Were primary and secondary endpoints described and relevant to the question?	Yes
	7.2.	Were nutrition measures appropriate to question and outcomes of concern?	Yes
	7.3.	Was the period of follow-up long enough for important outcome(s) to occur?	Yes
	7.4.	Were the observations and measurements based on standard, valid, and reliable data collection instruments/tests/procedures?	Yes
	7.5.	Was the measurement of effect at an appropriate level of precision?	Yes
	7.6.	Were other factors accounted for (measured) that could affect outcomes?	Yes
	7.7.	Were the measurements conducted consistently across groups?	Yes
8.	Was the statistical analysis appropriate for the study design and type of outcome indicators?		Yes
	8.1.	Were statistical analyses adequately described and the results reported appropriately?	Yes
	8.2.	Were correct statistical tests used and assumptions of test not violated?	???
	8.3.	Were statistics reported with levels of significance and/or confidence intervals?	???
	8.4.	Was "intent to treat" analysis of outcomes done (and as appropriate, was there an analysis of outcomes for those maximally exposed or a dose-response analysis)?	Yes
	8.5.	Were adequate adjustments made for effects of confounding factors that might have affected the outcomes (e.g., multivariate analyses)?	Yes
	8.6.	Was clinical significance as well as statistical significance reported?	Yes
	8.7.	If negative findings, was a power calculation reported to address type 2 error?	N/A
9.	Are conclusions supported by results with biases and limitations taken into consideration?		Yes
	9.1.	Is there a discussion of findings?	Yes
	9.2.	Are biases and study limitations identified and discussed?	Yes
10.	Is bias due to study's funding or sponsorship unlikely?		Yes
	10.1.	Were sources of funding and investigators' affiliations described?	Yes
	10.2.	Was the study free from apparent conflict of interest?	Yes