Questions regarding the progesterone pharmacokinetic study.

13 10 2009

To the Editor:

We disagree with the results of the trial by Blake et al. (1) with regard to the pharmacokinetics of Crinone and Endometrin.

Subjects in their study were healthy fertile women with normal ovulatory cycles and progesterone levels. Progesterone levels vary considerably in normal menstrual cycles, and dosing occurred day 5-8 (1-day dosing) and 7 days later in the luteal phase (multi-day dosing). Therefore, a significant part of the measured progesterone was most likely endogenously produced.

Even if we assume that none of the measured progesterone was endogenous, the data suggest that the blood sample collection may not have adequately estimated the peak and total systemic exposure for Crinone. The estimates for Crinone total systemic exposure by Blake (1) are substantially lower than previously reported (2) (Crinone label). In the Blake paper (1), the mean area under the curve (AUC0-24) (Table 2) was 81 ng-h/mL and 264 ng-h/mL following single- and multiple-dose administration, respectively. The corresponding values reported previously were 133 ng-h/mL2 and 167 ng-h/mL (Crinone label, calculated from Cavg 0-24 data) following single dose and 392 ng-h/mL (Crinone label) following multiple doses. An explanation for this discrepancy is the lack of a 6-hour blood sample. With Crinone, the Tmax for progesterone in the previous studies approximated 5-7 hours (compared with 12-13 hours in the present study). The shape of the concentration-time curves for Crinone in figures 1 and 3 supports the conclusion that systemic exposure may not have been adequately estimated.

Also, variability of total exposure was not reported. The coefficients of variation for the AUC0-24 values for the single dose are calculated to be 52.1%, 50.4% and 51.4% for the insert b.i.d., insert t.i.d. and Crinone, respectively, and 38.8%, 24.3% and 42.7% following multiple doses. Therefore, variances in the pharmacokinetic parameters are similar and substantial for all formulations, resulting in the low power of this study to distinguish between treatments, given the small sample size and non-crossover design.

Furthermore, there are few data to support the assertion that a progesterone level of 10 ng/mL is associated with good outcomes in an IVF cycle. On the contrary, the consensus is that blood progesterone levels do not correlate with pregnancy outcome in an IVF cycle. (3,4)

Finally, the large clinical trial referenced by Blake et al. (5) found a primary efficacy result for ongoing pregnancy of 42% for Crinone, 42% for Endometrin t.i.d., and 39% for Endometrin b.i.d., leading us to question the conclusions of the present study.

Larry S. Abrams, Ph.D.
Brian M. Berger, M.D.
Boston IVF/Harvard Medical School
Quincy, Massachusetts

References
1. Emily J. Blake, Paul M. Norris, Sally Faith Dorfman, James Longstreth, Vladimir I. Yankov. Single and multidose pharmacokinetic study of a vaginal micronized progesterone insert (Endometrin) compared with vaginal gel in healthy reproductive-aged female subject. Fertility and Sterility [epub ahead of print]
DOI: 10.1016/j.fertnstert.2009.06.014

2. Levine H, Watson N. Comparison of the pharmacokinetics of Crinone 8% administered vaginally versus prometrium administered orally in postmenopausal women. Fertility and Sterility, 2000; 73(3): 516-521

3. Chantilis SJ, Zeitoun KM, Patel SI, et al. Use of Crinone vaginal progesterone gel for luteal support in in vitro fertilization cycles. Fertil Steril. 1999;72:823–829.

4. Williams SC, Donahue J, Muasher SJ. Vaginal progesterone therapy during programmed cycles for frozen embryo transfer: an analysis of serum progesterone levels and pregnancy rates. Fertil Steril. 2000;74(suppl 1):S209. Abstract P-363.

5. Doody KJ, Schnell VL, Foulk RA, Miller CE, Kolb BA, Blake EJ, Yankov VI. Endometrin® for luteal phase support in a randomized, controlled, open-label, prospective IVF clinical trial using a combination of Menopur® and Bravelle®. Fertil Steril. 2009; Apr;91(4):1012-7.

Published online in Fertility and Sterility doi:10.1016/j.fertnstert.2009.10.018

The Authors Respond:

We wish to correct the misperceptions stated in the response letter to the pharmacokinetics study of Crinone and Endometrin (1). The results showed that Endometrin rapidly produced higher progesterone serum concentrations, achieved greater systemic exposure, reached steady-state more rapidly, and cleared sooner after termination of therapy than Crinone.

Regarding the comment on time of peak concentration, sustained-release dosage forms are generally intended to yield a concentration-time profile with a broad, flat peak or plateau. Therefore, Tmax may have any of a wide range of values, since the maximum observed concentration will be the one with the largest positive random excursion from that plateau’s nominal value. In support of the profile for Crinone being such a plateau, three subjects had Tmax at 12 hours or greater and three had Tmax at four hours or earlier during the multiple dosing. As displayed in Figure 1 (1), mean Crinone concentrations were uniform over the entire 24-hour dosing interval, thus, focusing on a specific value for the Crinone Tmax has little clinical utility. The clinical or pharmacokinetic significance of a difference in mean (or median) Tmax of 6 versus 12 hours is questionable in this setting.

Second, the correspondents question the suitability of the sampling protocol, claiming that the Crinone label gives an AUC0-24 on Day 1 of 167 ng-hr/mL and after multiple doses, 392 ng-hr/mL, as compared with the values reported in our paper of 81 and 264 ng-hr/mL. However, the value for AUC0-24 under multiple dosing conditions in the 10-year-old Crinone label is actually 216 ng-hr/mL instead of the 392 cited by the correspondents. The 392 value comes from the table entry for the AUC0-t, which is not the same as AUC0-24. AUC0-24 must be calculated from the Cavg value (i.e., 8.99 ng/mL*24 hours). The AUC0-t, which is the area to the last quantified or quantifiable concentration, would be expected to be substantially larger than the AUC0-24. Since 216 is not numerically greater than 264, the argument that not including a six-hour sampling time might explain our “low” observed concentrations is invalid.

Regarding the argument that the high variability (CV) observed in the study precludes drawing any conclusions about differences between treatments; while exposure values were greater with Endometrin, not surprisingly statistical significance was not reached, given the intentionally small subject population. Pharmacokinetics studies designed to elucidate dose-concentration relationships under single or multiple dose conditions typically use 6-8 subjects. This sample size is a compromise between being large enough that the mean value is representative of a larger population, while minimizing unnecessary exposure of healthy people to a medicinal agent. The study design was consistent with standard practice for meeting the study objectives. As stated in the article, “Limitations to our study include the small sample size and considerable coefficient of variability.”

James Longstreth, Ph.D.
Longstreth & Associates, Inc.
Mundelein, Illinois

Sally Faith Dorfman, M.D., MSHSA
Vladimir Yankov, M.D.
Ferring Pharmaceuticals Inc.
Parsippany, New Jersey

Reference
1. Blake E, Norris P, Dorfman S, Longstreth J, Yankov V. Single and multidose pharmacokinetic study of a vaginal micronized progesterone insert (Endometrin®) compared to vaginal gel in healthy reproductive-aged female subjects. Fertil Steril in press.

Published online in Fertility and Sterility doi:10.1016/j.fertnstert.2009.10.017

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