Mechanism Of Action
Hydroxyprogesterone caproate is a synthetic progestin. The mechanism by which hydroxyprogesterone caproate reduces the risk of recurrent preterm birth is not known.
No specific pharmacodynamic studies were conducted with Makena.
Female patients with a singleton pregnancy received intramuscular doses of 250 mg hydroxyprogesterone caproate for the reduction of preterm birth starting between 16 weeks 0 days and 20 weeks 6 days. All patients had blood drawn daily for 7 days to evaluate pharmacokinetics.
Table 4 Summary of Mean (Standard Deviation) Pharmacokinetic Parameters for Hydroxyprogesterone Caproate
||AUC(0-t) b (ng·hr/mL)
|Group 1 (N=6)
|Group 2 (N=8)
|Group 3 (N=11)
|Blood was drawn daily for 7 days (1) starting 24 hours after the first dose between Weeks 16-20 (Group 1), (2) after
a dose between Weeks 24-28 (Group 2), or (3) after a dose between Weeks 32-36 (Group 3)
a Reported as median (range)
b t = 7 days
For all three groups, peak concentration (Cmax) and area under the curve (AUC(1-7 days)) of the mono-hydroxylated metabolites were approximately 3-8-fold lower than the respective parameters for the parent drug, hydroxyprogesterone caproate. While di-hydroxylated and trihydroxylated metabolites were also detected in human plasma to a lesser extent, no meaningful quantitative results could be derived due to the absence of reference standards for these multiple hydroxylated metabolites. The relative activity and significance of these metabolites are not known.
The elimination half-life of hydroxyprogesterone caproate, as evaluated from 4 patients in the study who reached full-term in their pregnancies, was 16.4 (±3.6) days. The elimination half-life of the mono-hydroxylated metabolites was 19.7 (±6.2) days.
In a single-dose, open-label, randomized, parallel design bioavailability study in 120 healthy post-menopausal women, comparable systemic exposure of hydroxyprogesterone caproate was seen when Makena was administered subcutaneously with the auto-injector (1.1 mL) in the back of the upper arm and when Makena was dosed intramuscularly (1 mL) in the upper outer quadrant of the gluteus maximus.
Hydroxyprogesterone caproate binds extensively to plasma proteins including albumin and corticosteroid binding globulins.
In vitro studies have shown that hydroxyprogesterone caproate can be metabolized by human hepatocytes, both by phase I and phase II reactions. Hydroxyprogesterone caproate undergoes extensive reduction, hydroxylation and conjugation. The conjugated metabolites include sulfated, glucuronidated and acetylated products. In vitro data indicate that the metabolism of hydroxyprogesterone caproate is predominantly mediated by CYP3A4 and CYP3A5. The in vitro data indicate that the caproate group is retained during metabolism of hydroxyprogesterone caproate.
Both conjugated metabolites and free steroids are excreted in the urine and feces, with the conjugated metabolites being prominent. Following intramuscular administration to pregnant women at 10-12 weeks gestation, approximately 50% of a dose was recovered in the feces and approximately 30% recovered in the urine.
Cytochrome P450 (CYP) Enzymes
An in vitro inhibition study using human liver microsomes and CYP isoform-selective substrates indicated that hydroxyprogesterone caproate increased the metabolic rate of CYP1A2, CYP2A6, and CYP2B6 by approximately 80%, 150%, and 80%, respectively. However, in another in vitro study using human hepatocytes under conditions where the prototypical inducers or inhibitors caused the anticipated increases or decreases in CYP enzyme activities, hydroxyprogesterone caproate did not induce or inhibit CYP1A2, CYP2A6, or CYP2B6 activity. Overall, the findings indicate that hydroxyprogesterone caproate has minimal potential for CYP1A2, CYP2A6, and CYP2B6 related drug-drug interactions at the clinically relevant concentrations.
In vitro data indicated that therapeutic concentration of hydroxyprogesterone caproate is not likely to inhibit the activity of CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4.
Clinical Trial To Evaluate Reduction Of Risk Of Preterm Birth
In a multicenter, randomized, double-blind, vehicle (placebo)-controlled clinical trial, the safety and effectiveness of Makena for the reduction of the risk of spontaneous preterm birth was studied in women with a singleton pregnancy (age 16 to 43 years) who had a documented history of singleton spontaneous preterm birth (defined as delivery at less than 37 weeks of gestation following spontaneous preterm labor or premature rupture of membranes). At the time of randomization (between 16 weeks, 0 days and 20 weeks, 6 days of gestation), an ultrasound examination had confirmed gestational age and no known fetal anomaly. Women were excluded for prior progesterone treatment or heparin therapy during the current pregnancy, a history of thromboembolic disease, or maternal/obstetrical complications (such as current or planned cerclage, hypertension requiring medication, or a seizure disorder).
A total of 463 pregnant women were randomized to receive either Makena (N=310) or vehicle (N=153) at a dose of 250 mg administered weekly by intramuscular injection starting between 16 weeks, 0 days and 20 weeks, 6 days of gestation, and continuing until 37 weeks of gestation or delivery. Demographics of the Makena-treated women were similar to those in the control group, and included: 59.0% Black, 25.5% Caucasian, 13.9% Hispanic and 0.6% Asian. The mean body mass index was 26.9 kg/m2.
The proportions of women in each treatment arm who delivered at < 37 (the primary study endpoint), < 35, and < 32 weeks of gestation are displayed in Table 5.
Table 5 Proportion of Subjects Delivering at < 37, < 35 and < 32 Weeks Gestational Age (ITT Population)
|Treatment difference and 95% Confidence Interval2
||-17.8% [-28.0%, -7.4%]
||-9.4% [-19.0%, -0.4%]
||-7.7% [-16.1%, -0.3%]
|1 Four Makena-treated subjects were lost to follow-up. They were counted as deliveries at their gestational ages at time of last contact (184, 220, 343 and 364 weeks).
2 Adjusted for interim analysis.
Compared to controls, treatment with Makena reduced the proportion of women who delivered preterm at < 37 weeks. The proportions of women delivering at < 35 and < 32 weeks also were lower among women treated with Makena. The upper bounds of the confidence intervals for the treatment difference at < 35 and < 32 weeks were close to zero. Inclusion of zero in a confidence interval would indicate the treatment difference is not statistically significant. Compared to the other gestational ages evaluated, the number of preterm births at < 32 weeks was limited.
After adjusting for time in the study, 7.5% of Makena-treated subjects delivered prior to 25 weeks compared to 4.7% of control subjects; see Figure 1.
Figure 1 Proportion of Women Remaining Pregnant as a Function of Gestational Age
The rates of fetal losses and neonatal deaths in each treatment arm are displayed in Table 6. Due to the higher rate of miscarriages and stillbirths in the Makena arm, there was no overall survival difference demonstrated in this clinical trial.
Table 6 Fetal Losses and Neonatal Deaths
n (%) B
n (%) B
|Miscarriages <20 weeks gestation C
| Antepartum stillbirth
| Intrapartum stillbirth
A Four of the 310 Makena-treated subjects were lost to follow-up and stillbirth or neonatal status could not be
B Percentages are based on the number of enrolled subjects and not adjusted for time on drug
C Percentage adjusted for the number of at risk subjects (n=209 for Makena, n=107 for control) enrolled at <20
A composite neonatal morbidity/mortality index evaluated adverse outcomes in live births. It was based on the number of neonates who died or experienced respiratory distress syndrome, bronchopulmonary dysplasia, grade 3 or 4 intraventricular hemorrhage, proven sepsis, or necrotizing enterocolitis. Although the proportion of neonates who experienced 1 or more events was numerically lower in the Makena arm (11.9% vs. 17.2%), the number of adverse outcomes was limited and the difference between arms was not statistically significant.
Infant Follow-Up Safety Study
Infants born to women enrolled in this study, and who survived to be discharged from the nursery, were eligible for participation in a follow-up safety study. Of 348 eligible offspring, 79.9% enrolled: 194 children of Makena-treated women and 84 children of control subjects. The primary endpoint was the score on the Ages & Stages Questionnaire (ASQ), which evaluates communication, gross motor, fine motor, problem solving, and personal/social parameters. The proportion of children whose scores met the screening threshold for developmental delay in each developmental domain was similar for each treatment group.