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CLINICAL STUDIES |
From the Departments of Emergency Medicine (Dr Wright, Dr Kellermann), Anesthesiology (Dr Denson), and Pathology and Laboratory Medicine (Dr Ritchie, Dr Mullins), Emory University School of Medicine, Atlanta, Georgia.
Address for reprints: David W. Wright, Department of Emergency Medicine, Emory University School of Medicine, Emergency Medicine Research Center, 49 Jessie Hill Jr Drive, Atlanta, GA 30303.
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Key Words: Traumatic brain injury • pharmacokinetics • continuous infusion • progesterone
Despite the enormity of the problem, an effective pharmacological treatment for TBI in humans has not been identified. Animal studies using progesterone as an acute postinjury treatment have found that it reduces cerebral edema, neuronal loss, and behavioral deficits following TBI.6-15 These data were compelling enough to justify a pilot clinical trial in humans to test the safety and potential efficacy of progesterone as a neuroprotectant in acutely brain-injured patients. Unfortunately, there are no reports regarding the pharmacokinetics of progesterone in acutely injured TBI patients. Delayed gastrointestinal absorption, first-pass hepatic metabolism, and an altered mental state limit the feasibility of the oral route.16-21 Enteral administration by vaginal or rectal suppository and subcutaneous and intramuscular absorption are potentially altered in shock states, a common problem for major trauma patients.22,23
Continuous intravenous (IV) infusion allows rapid drug delivery and achievement of a continuous steady-state serum concentration, but this route for administration of progesterone is not approved by the Food and Drug Administration (FDA) in the United States. Only 3 human studies involving the use of IV progesterone in the United States have been reported. In an FDA-approved (Investigational New Drug [IND] 33,580) phase I clinical trial, Christen et al administered IV progesterone dissolved in an ethanol-Intralipid 20% fat emulsion combined with doxorubicin over 24 hours to 32 cancer patients without toxic effects.24 In a second study, Allolio et al reported that steady-state serum concentrations (CSS) of progesterone could be achieved in healthy male volunteers infusing 0.714 mg/kg IV over the first hour (loading dose) followed by 0.45 mg/kg/h for a total infusion time of approximately 5 hours.25 The third study was modeled after the study performed by Christen et al but was a phase II trial testing the effect of coadministration of high-dose progesterone on the pharmacokinetics of paclitaxel. The article did not present detailed information on the pharmacokinetics of progesterone. There were no reported adverse outcomes related to progesterone co-administration with this drug.26
In an effort to determine whether the pharmacokinetic characteristics of progesterone following continuous intravenous infusion are altered in TBI, we conducted an FDA-approved, randomized, double-blind, placebo-controlled study. Based on the 2 published studies that included pharmacokinetic data, we hypothesized that a steady-state serum progesterone concentration (CSS) of 450 ± 100 ng/ml could be achieved and maintained using a standard loading and maintenance infusion paradigm over 72 hours.24,25
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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18 years old, have a closed head injury arising from blunt trauma, have a moderate to severe brain injury (Index Glasgow Coma Score [GCS] 4-12), and arrive in the emergency department and give informed consent (from next of kin) in less than 11 hours postinjury. Exclusion criteria included nonsurvivable injury, no neurological activity (GCS 3), mild TBI (index GCS 13-15), unknown time of injury, severe intoxication (ethyl alcohol 250 mg%), spinal cord injury with neurodeficits, cardiopulmonary arrest, status epilepticus on arrival, blood pressure <90 systolic on arrival or for 5 minutes in duration prior to enrollment, hypoxia on arrival, pO2 <60 on arrival or for 5 minutes in duration prior to enrollment, women who were pregnant, active breast or reproductive organ cancers, or known allergy to progesterone or Intralipid components (egg yolk or soy oil).
Drug Preparation
Solutions of study drug were prepared by the Investigational Drug Service of Emory Healthcare as follows: progesterone was dissolved in 95% ethanol and filtered into sterile vials using a 0.2-µ filter. Aliquots of each solution were assayed for final concentration and sterility. Stock solutions of progesterone/placebo were packaged in kits (A, B, C, D, or E) that matched the randomized treatment assignments. Each kit contained 6 vials. Vial 1 contained 15 mL of progesterone or placebo, which was used to prepare the initial bolus and first infusion dose. The remaining 5 vials contained 12 mL of progesterone or placebo for the remaining infusions. Since progesterone is soluble only in alcohol, the diluent used to compound the progesterone solution was 95% ethanol. The placebo kits were also formulated with 95% ethanol. Because of the alcohol concentration, doses of study drug were mixed with Intralipid immediately prior to infusion. Each infusion dose was administered over 12 hours and repeated every 12 hours, for a total of 72 hours. After randomizing a patient, a dosing worksheet based on body weight and final progesterone concentration was used to determine the volume of vial 1 required to be diluted in Intralipid for a standard loading infusion rate (14 cc/h) and the first 11 hours of the maintenance infusion (10 cc/h). The dosing worksheet was also used to calculate the volume of study medication to be diluted in Intralipid for each of the remaining infusion reservoirs at a standard rate of 10 cc/h.
Stability of Progesterone Solutions
For all stability testing, the method of Segall et al was used with minor modifications.27 The method was originally validated to assess the stability of medroxyprogesterone acetate and estradiol valerate tablets. It is an isocratic high-performance liquid chromatography (HPLC)–ultraviolet method using external standardization. A 5 µm, 4.6 x 250 mm BDS-Hypersil C-18 column (Keystone Scientific, Bellefonte, Pa) was used, and the analyses were completed on an Agilent 1100 model HPLC system with photodiode array detector. The mobile phase consisted of 40% 0.07 M ammonium acetate buffer, pH 7.2, and 60% acetonitrile. Detection was at 247 nm. A check of system suitability yielded 2769 plates per meter (minimum requirement >2500) based on the progesterone peak and a relative standard deviation of 0.80% (minimum requirement 1.0% or less). The tailing factor for the progesterone peak was 0.5. Reproducibility as assessed by 10 injections of the same preparation on multiple days was always less than 10%.
For each assay, progesterone preparations were diluted 1 to 10 with ethanol, and 1 µL of this dilution was injected. Under these conditions, progesterone eluted at roughly 3.5 minutes. A 5-point standard curve was run with each analysis.
For stability testing, preparations were analyzed initially in duplicate. The samples were then resealed and stored at room temperature in the dark for various periods. For repeat analysis, the preparations were opened and fresh dilutions were prepared and assayed in duplicate.
Drug Administration
The progesterone study drug solution was infused at the loading rate of 14 mLs/h (0.71 mg/kg/h) for 1 hour, followed by a decrease in infusion rate to 10 mLs/h (0.5 mg/kg/h) for the remaining 71 hours. Although Intralipid solutions containing progesterone were found to be stable for a minimum of 24 hours, reservoirs of study drug were prepared and changed every 12 hours during the infusion period to minimize the risk of biological contamination. Any interruptions in drug administration or other deviations from the protocol were noted on a drug administration flow sheet and taken into account when calculating the total number of milligrams of progesterone actually administered to each patient.
Sampling Paradigm
Nine (5 mL) samples were obtained at the following times during the infusion: preinfusion (0), 4, 6, 12, 24, 36, 48, 60, and 72 hours. An additional 5 samples were obtained following cessation of infusion at 0.5, 1, 2, 4, and 8 hours. Samples were allowed to clot and then centrifuged. After that, the serum was removed and stored at –70°C until analyzed.
Serum Progesterone Analysis
Serum progesterone concentrations were measured using the Immulite progesterone chemi-luminescent enzyme immunoassay by the Immunology Laboratory of the Department of Pathology, Emory University Hospital. The within- and between-day coefficients of variation for the assay were both <10%. We confirmed the accuracy of our assay by comparing the results of 9 samples over the range 0.5 to 700 ng/mL assayed in our laboratory with those assayed by a reference laboratory (The Nichols Institute, San Juan Capistrano, Calif).
Pharmacokinetic Analysis
The primary pharmacokinetic parameter, clearance (CL), was estimated as the ratio of the dose to area under the serum concentration-time curve (AUC). AUCs were calculated using the linear trapezoidal rule.28 The elimination phase rate constant, ke, was calculated from the serum concentration-time data following the termination of the infusion using iterative nonlinear regression (WinNonlin; Pharsight Corporation, Mountain View, Calif). Volume of distribution was estimated as the ratio of CL and ke.CSS was estimated as the ratio of dose and CL. Actual CSS was defined as the concentration achieved when the slope of the serum concentration-time curve for 3 or more consecutive samples was not different from zero.
Statistical Analysis
A t test for repeated measures and a Spearman's rank correlation coefficient were used to compare the progesterone concentrations measured by our laboratory with those measured by the Nichols Institute. Predicted CSS concentrations were calculated as the ratio of the infusion rate/clearance. Differences between predicted and measured CSS were made using a t test for repeated measures. A Bland-Altman analysis was conducted to assess the magnitude of any bias associated with this approach.29 Pharmacokinetic parameter comparisons between men and women were accomplished using a t test for independent means. A P value of less than .05 was considered the minimum level for rejection of the null hypothesis.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Table I is a summary of the demographic and primary pharmacokinetic data stratified by gender. There were no significant differences between men and women with respect to any of the parameters in Table I with the exception of body weight. As one might expect, the mean body weight for the men (81.5 ± 16.2 kg) was significantly greater (P < .003) than that for the women (63.9 ± 11.0 kg). CL values were calculated from the total dose of progesterone infused and the AUC(0-72 h) rather than from AUC(0-
) because complete postinfusion blood sampling was not possible in a number of the patients for medical reasons. The mean value for CL was found to be 1.73 ± 0.72 L/kg/h and was not different in men (1.66 ± 0.67 L/kg/h) and women (1.88 ± 0.81 L/kg/h). Although a direct comparison is not possible because we did not record heights in our patients and therefore could not calculate body surface areas, CL values in the current study are higher than expected for those reported for progesterone infusions in cancer patients.24 Using the value for progesterone CL from the current serum concentration-time data did not result in any statistically significant differences between the CSS values predicted by Ro/CL (332 ± 121 ng/mL) and those actually measured (337 ± 135 ng/mL) and were not different for men or women. Figure 2 is a summary of measured and predicted CSS values plotted against the line of identity. The Spearman rank correlation coefficient for this relationship was 0.946 (P < .001). The significance of the relationship was confirmed using a Bland-Altman analysis, which revealed no systematic bias between the measured and predicted CSS values. The relative difference between predicted and measured CSS was –0.8% ± 12.2% (see Figure 3). Figure 4 is a plot of measured CSS for each patient showing that these concentrations were systematically lower than the target concentration range predicted from previous studies.24,25 These data suggest that in trauma patients with moderate to severe head injuries, the resulting hyperkinetic physiologic state results in a clinically significant increase in progesterone clearance. These data suggest that to achieve our target concentration of 450 ± 100 ng/mL, the maintenance infusion rate should be increased from 0.5 mg/kg/h to approximately 0.8 mg/kg/h.
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The mean value for terminal half-life was found to be 1.78 ± 1.0 hour. Once again, there were no differences between men (1.60 ± 0.95 hours) and women (2.03 ± 1.08 hours; P < .4) These values are somewhat longer than those reported in cancer patients.24 Volumes of distribution (Vd) in the current study are higher than expected from previous reports because of the elevation in CL and decrease in terminal elimination phase rate constant. Although values for men tended to be lower, Vds were not significantly different for men (3.76 ± 2.14 L/kg) and women (5.76 ± 4.21 L/kg; P < .22).
It is important to remember that these were critically injured patients, many of whom were receiving multiple drugs to stabilize their condition. We tracked all drugs received during the patients' first 30 days of hospitalization or until patient discharge (whichever came first). The drugs tracked included propofol, midazolam, fentanyl, haloperidol, thiopental, pentobarbital, lorazepam, phenylephrine, desmopressin, dopamine, acetaminophen, morphine, succinylcholine, vecuronium, mannitol, hypertonic saline, and any others charted. A search of drug interaction databases did not reveal any clinically significant interactions between any of the drugs listed above and progesterone. The combination of drugs was individualized based on each patient's specific medical needs, and no consistent combination of the above drugs was given to all (or a majority) of patients.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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A substantial and rapidly growing body of data indicates that the hormone progesterone, a neurosteroid that is naturally found in the brains of men and women, has potent neuroprotective properties. The data presented in this article were obtained during the first pilot, randomized controlled clinical trial of progesterone for treatment of moderate to severe acute TBI. In addition to testing whether the drug is safe and efficacious for this condition, we sought to determine the pharmacokinetic properties of intravenous progesterone in multisystem trauma patients.
The major findings of our investigation are (1) a solution of progesterone in 95% ethyl alcohol is stable for up to 2 years at room temperature; (2) Intralipid solutions containing progesterone in 95% ethyl alcohol are stable for a minimum of 24 hours; (3) a CSS of progesterone can be rapidly achieved and maintained in acute, critically ill traumatic brain-injured patients with multisystem trauma using a 2-phase IV infusion paradigm; (4) progesterone CSS values can be accurately predicted from AUC data; (5) the hyperkinetic physiologic alterations accompanying acute TBI result in significant elevations in CL, t1/2, and Vd for progesterone; (6) acute TBI, per se, does not result in endogenous release of progesterone; and (7) alterations in progesterone pharmacokinetics following acute TBI are not gender dependent. One of the most important goals in clinical pharmacokinetics is obtaining patient-specific estimates of the appropriate pharmacokinetic parameters. The use of model-independent methods (AUC) is extremely robust for determining patient-specific CL. CL is the primary parameter of interest when drugs are being administered by continuous intravenous infusion since the resultant patient-specific CSS is dependent only on infusion rate and CL.
The current study demonstrates that stable CSS values of progesterone were rapidly achieved with IV administration, making dosing adjustments to realize a target concentration practical in a population of critically injured patients regardless of gender. While the number of patients in this investigation receiving a placebo infusion is small, repeated sampling and analysis show that the initial progesterone concentrations are constant over the 84-hour time course of study. These data suggest that endogenous secretion of progesterone is not significantly stimulated by TBI per se. The ultimate goal, of course, is to define the CSS that correlates with optimum treatment efficacy. Once the pharmacodynamic relationship between steady-state serum concentration of progesterone and clinical outcome is elucidated, the parameters determined in our study may be used to draft an infusion paradigm that optimizes the odds of survival and functional recovery. Since the CSS are rapidly achieved and are stable, patient-specific adjustments in infusion rate to maintain a target concentration should be possible with minimal early blood sampling. If such a pharmacologic intervention proves efficacious, our stability data demonstrate that stock solutions of progesterone in ethanol, which are tedious to prepare, can be safely used for up to 2 years. This would allow neurotrauma units immediate access to progesterone solutions and facilitate rapid treatment implementation.
In 1993, the Brain Injury Foundation convened an international task force to develop evidence-based guidelines for treatment of traumatic brain injury.32-34 With the exception of mannitol and barbiturates, no pharmacological agents were identified that enhance recovery.
Animal studies of progesterone's effects on TBI have consistently found that it reduces edema, neuronal loss, and behavioral deficits.6-15 Moreover, there are several reasons to believe that progesterone may be an ideal agent for treatment in humans. Progesterone rapidly enters the brain and reaches equilibrium with the plasma within 1 hour of administration.35 The drug has no appreciable effects on heart rate, blood pressure, respiratory drive, coagulopathy, or infection rate, important considerations in critically injured patients. Based on animal research, progesterone may have a therapeutic window up to 24 hours postinjury.14 The drug has a history of safe use in men as well as women for a wide variety of medical conditions.25,36,37 Finally, because the drug is available in generic forms, it is inexpensive.
Clinically significant drug-drug interactions have not been reported between progesterone and a large number of other drugs.38,39 In the current study, additional drugs were coadministered to optimize the medical management of these critically injured patients. The drug combinations and dosing regimens were individualized on a patient-specific basis. As such, there was not a consistent group of these drugs given to all patients. Because a number of the additional drug classes, in particular, the anticonvulsants and barbiturates, can result in altered physiology including increases in hepatic blood flow and increases in oxidative metabolism, we cannot unequivocally determine whether the increased values for progesterone clearance are a result of concomitant drug administration or TBI.
Using the results from this study coupled with future findings from a dose-response efficacy trial, investigators should be able to adjust infusion rates of progesterone to achieve optimal steady-state concentrations. If intravenous infusion of progesterone proves to produce benefits in acutely brain-injured humans comparable to those reported in animals, this will represent a major advance in the treatment of this common and devastating condition.
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ACKNOWLEDGEMENTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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REFERENCES |
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