COMPARATIVE COPPER PHARMACOKINETIC PROPERTIES OF A NOVEL LOW-DOSE NITINOL FRAME COPPER INTRAUTERINE DEVICE (IUD) AND THE COPPER T380A IUD: A RANDOMIZED CONTROLLED TRIAL

Abstract

We compared the pharmacokinetics and bioavailability of serum copper in women receiving either a novel low-dose nitinol frame copper IUD or the copper T380A IUD through the first 57 days of use. Two sites participated in this parallel -single-blind study that randomized reproductive age women 1:1 to an investigational low-dose copper IUD (with 175 mm2 of exposed copper) or the approved copper T380A (Paragard, 380 mm2) IUD. Participants provided two baseline total serum copper samples at least 24 hours apart within 28 days prior to IUD placement followed by seven samples following randomization on days 1, 3, 8, 15, 22, 29, and 57. We used a noncompartmental mixed-effects linear analysis of variance (ANOVA) model with treatment as a fixed effect and subject as a random effect to calculate uncorrected PK parameters Cmax, Cmean, and AUC0-56 days. We compared relative bioavailability between the two groups by geometric mean ratios and 90% confidence intervals. We hypothesized that the relative bioavailability of total serum copper for the low-dose device would not exceed established normal (490 to 1840 ng/ml) or levels seen in users of the copper T380A. Of the 41 participants enrolled, 39 had successful IUD placements (20 in the low-dose group and 19 in the T380A group) with 36 of those subjects completing the treatment comparison phase of the study (19 low-dose and 17 T380A). Participants reported a mean age of 28.4 years. The baseline mean serum copper concentrations for the low-dose group were 1220 ng/ml standard deviation (SD) ± 285 ng/ml vs. 1250 ng/ml ± 276 ng/ml for the T380A group. Observed copper concentrations in both groups remained in the normal range; with the relative mean Cmax, Cmean, and AUC 0-56 days of 1210 ng/ml, 1070 ng/ml, and 59,700 for the low-dose IUD group vs. 1300, 1150, and 63,600 for the T380A group. Post IUD placement values for both the low-dose group and the copper T380A group were slightly lower than baseline values over the seven timepoints from 0-56 days. Respective baseline-corrected mean values for the low-dose group were 7.8 to 29.8 ng/ml and for the T380A group were 14.9 to 34.3 ng/ml lower than baseline. Relative bioavailability by geometric mean copper exposure for all parameters ranged from 0.93-0.94 (90% CI for all values 0.85-1.02) with all mean values for the low-dose IUD lower than the T380A. Serum copper concentrations for the two IUDs remained within the normal range and trended toward lower values for participants assigned to the low-dose copper IUD relative to the T380A. Neither IUD generated clinically meaningful changes in total serum copper concentrations during the first 56 days after IUD placement.