Why Lupron Metabolism is Important
Metabolism is a pharmacokinetic parameter that refers to the rate and process by which drugs are cleared from the body. Pharmacokinetic studies determine how the drug is absorbed, distributed, metabolized and excreted, or ADME for short. ADME determines the dosing, safety (overdosing), and efficacy of a drug. How the drug is metabolized is particularly important. This includes determining which enzymes are used (and which other drugs compete with those enzymes) and which metabolites develop. Sometimes, the metabolite of a drug is more active than the original drug and so what effect those metabolites have and how long they take to clear should be considered as well. These issues should resolved before a drug receives FDA approval. If those questions are not answered, there is no way to determine the safety or the efficacy of a drug. Lupron’s approval came without the requisite metabolism studies. According the manufacturers own drug labels, approved by the FDA, pharmacokinetics were unclear upon its release in men (1985), women (1990), and children (1993; *1994 pediatric Lupron Depot label shown above). Upon release and in the years subsequent, it was acknowledged,
“…the exact mechanism(s) of action has not been fully elucidated … [and] may involve inhibition and/or induction of enzymes that control steroidogenesis” .
Historically, the Lupron labels have stated,
“No pharmacokinetic-based drug-drug interaction studies have been conducted; however, drug interactions are not expected to occur”.
How was a drug that influences so many physiological systems approved without understanding the most basic pharmacokinetic parameters?
What the FDA Knew When?
The labels, or package inserts, of Lupron Depot provide a chronology of what the manufacturer knew and/or identified. I possess many (but not all) labels for the various years, indications, dosages, and formulations, and from these available labels, the following pertinent highlights are provided.
Lupron for Prostate Cancer
When Lupron was first approved for men in 1985 for palliative treatment of prostate cancer (the daily formulation), its product label included the following:
“Leuprolide acetate has a plasma half-life of approximately three hours. The metabolism, distribution and excretion of leuprolide acetate in man have not been determined.” (The reference to “plasma half-life of approximately three hours” was omitted in the 1988 daily label but was returned to the 1989 daily label; however the 1989 depot label lacks the reference to its plasma half-life.)
Lupron for Endometriosis
When Lupron Depot 3.75 mg was first approved for use in women, in 1990, the label included the following:
“Intramuscular injection of the depot formulation provides plasma concentrations of leuprolide acetate over a period of one month. … [L]euprolide is a peptide that is primarily degraded by peptidase [ ] … The metabolism, distribution and excretion of leuprolide acetate in humans have not been fully determined.”
During the FDA approval process for endometriosis, a reviewer asked: “[i]s the statement that leuprolide is degraded by peptides [sic] and not degraded by P-450 enzymes true? This statement contradicts the statement of page 7 which says that ‘The metabolism, distribution and excretion of leuprolide acetate in humans have not been fully determined’. Please clarify.” No clarification is provided within the received FOIA documents.
Lupron for Children
And when Lupron Depot-PED was first approved for children in 1993, the label included the following:
“In adults, intramuscular injection of the depot formulation provides plasma concentrations of leuprolide acetate over a period of one month. … [L]euprolide acetate is a peptide that is primarily degraded by peptidase [ ] … The metabolism, distribution and excretion of leuprolide acetate in humans have not been determined“.
A Decade Later – Information Added
As of 1997, all Lupron Depot and daily labels for men, women, and children indicated a drug half-life of approximately 3 hours (the time required for the drug concentration to decrease by half). And as of 1997, all Depot (but not daily) labels also contained newly added information about Lupron’s absorption, distribution, metabolism and excretion (change first noted in the 1995 female Depot label). For this discussion we will focus on metabolism.
Since drug metabolism has a high degree of inter-individual variability and can be affected by everything from the route of administration (oral versus IV, subcutaneous or intramuscular), to the age, sex and overall health of the participant, it is important that these studies be conducted in populations similar to those who would be using the drug (males versus females, for example), and should include a sufficiently large number of participants. In the case of Lupron, it does not appear that this was the case. Not only were the studies not conducted in advance of its release, or at least not published, but at least two of the three studies used to determine metabolism were significantly flawed.
Lupron Labels’ Metabolism Study #1
The study involved only six healthy men, using a one-time, relatively low dose, given intravenously and subcutaneously. Are the results from six healthy men robust enough to extrapolate to older, infirm men with prostate cancer? Might women and children metabolize a drug differently than healthy men? Might higher and repeat dosing affect metabolism? None of these issues were addressed. The study administered the drug intravenously and subcutaneously, but to my knowledge Lupron is routinely given subcutaneously (the daily injection Lupron) or intramuscularly (the depot preparations), and is given IV only within diagnostic purposes as a ‘challenge’ to the pediatric precocious puberty population.
So bear in mind the following: information about the metabolism of a drug to be used in children and women (and at higher doses), on a repeated basis, was determined by a study using six healthy men injected with a small dose only once. And these men were given intravenous and subcutaneous injections with the daily formulation of Lupron, whereas it is the depot formulation that is most often prescribed (which is administered intramuscularly). All this should give pause – and it doesn’t get better.
Initial Testing Methods Flawed
To the best of my knowledge, this study of six men was submitted to the FDA as a Bioavailability/Bioequivalence Study (M83-019) during the initial Lupron prostate clinical trials, however, the FDA found the methods used to determine plasma concentrations in this study “unacceptable mainly because the RIA assay employed was not fully validated.”
The FDA’s ‘Pharmacokinetics Evaluation Branch’ report states that normally this “deficiency must be resolved by the sponsor before the drug will be recommended for approval” (emphasis mine). However the FDA granted a deferral, allowing for the deficiencies to be resolved in a Phase IV period – and stated “[t]his deferral is granted on the basis of CFR 320.22e because Leuprolide is classified as a 1A drug.”
Yet the criteria of CFR 320.22e does not fit the circumstances, and despite assertions to the contrary Lupron is not classified by the FDA as a “1A drug”, but rather as a “1B drug”.
FDA documents do not provide an “Attachment 1”, identified as the manufacturer’s response to this study’s deficiencies, but in 1987 the FDA found this study acceptable. However, noteworthy within FDA’s ‘acceptance’ review are the following statements:
“There is no information on the metabolism of this drug. The firm’s protein binding data is not very reliable … they estimate less than 80% binding to human plasma.” Note that the initial (and subsequent) female and pediatric labels identify Lupron as “only about 46% bound to plasma proteins”. (Initial and early male labels lack protein binding data.)
Sketchy Half Life and AUC Calculations
In the medical literature’s publication of this study‘s results, the mean half-life from subcutaneous administration of Lupron was 4.07 hours (with a range of 2.7 to 6.8 hours), however, with some statistical smoothing, the study states the mean half-life was only 3.6 hours. Similarly troubling, the study reported
“a 2-fold difference between the highest and lowest AUC [area under curve] values and volumes of distribution [found, and] … there was appreciable subject-to-subject variability in distribution of the drug.” (p. 160)
These variations were
“probably a result of the drug kinetics being more complex than assumed, although no explanation is readily apparent.” (p. 159)
Two of the six men had high values for the fraction of drug reaching the general circulation, and
“[o]verall, the reason for the high value was not apparent, but most probably should be attributed to the combined experimental error in many variables.”
In the published reports of the data found in this one-time 1 mg bioavailability study, it was noted “the mean calculated peak circulating level [of subcutaneous Lupron] was 32.3 ng/mL, which was reached 0.6 h[ours] following administration.” An unrelated and separate study of women prescribed subcutaneous Lupron for fertility treatment reported similar serum concentration of Lupron (32.4 ng/mL) – but these female concentrations were noted at “one to two hours after Lupron administration” and not at “0.6 hours” as in the men. In addition, at a time that approximated 12 hours after Lupron was stopped (and exactly 35 hours before egg retrieval), serum concentrations of Lupron in this fertility study were calculated to be “44.6 ng/mL (+/- 5.6)”.
When Lupron’s labels state a half-life of ‘approximately 3 hours’, they are referencing the data from this study of six men. How can a study deemed initially unacceptable by the FDA – involving only six men – be touted in the pediatric, female, and every other drug label as evidence of Lupron’s clearance?
There have been other pharmacokinetic studies subsequently performed (as mentioned in various labels and as submitted in New Drug Applications), but Lupron’s labels continued to cite this 1 mg study on six men.
Lupron Labels’ Metabolism Study #2
This study is a Japanese study of rats and dogs, and is presumed to be published in “Jpn Pharmacol. Ther., 18 (Suppl. 3) (1990) S-545″. I have not yet been able to obtain or review it.
Lupron Labels’ Metabolism Study #3
All 1997 labels for Lupron Depot state:
“The major metabolite (M-I) plasma concentrations measured in 5 prostate cancer patients reached maximum concentration 2 to 6 hours after dosing and were approximately 6% of the peak parent drug concentration. One week after dosing, mean plasma M-I concentrations were approximately 20% of mean leuprolide concentrations.”
With a fair degree of certainty, I believe this information comes from this study using Lupron Depot 3.75 mg. The 3.75 mg dose has only been approved for females, and the standard dose for men has been 7.5 mg, so again, a low dose has been chosen to study in a handful of men. Note also that the work of this study “was supported by [Lupron’s manufacturer]”. The ‘Metabolism’ section of all 1997 Depot labels does not report that this study also found that:
“Leuprolide was detected in serum even four weeks after the injection” (p. 64), and “metabolites other than M-I could not be determined because antibodies against these metabolites have not yet been obtained” (p. 64).
How often do metabolites, as they break down and diminish in concentration, also increase in concentration? I don’t know the answer to that question, but do know, based upon the Tables (on p. 65) in this study (from one subject), that both urinary Lupron concentrations, and the major metabolite (M-I) concentrations decrease, then increase, then decrease, and increase again. Ten measurements were obtained during a 29-day study. In just one example of boomerang metabolite levels, Table IV of this study shows the urinary leuprolide (“UL”) and M-I-like immunoreactivity (“M-I) levels of one subject as follows:
- 1 day after Lupron – UL = 19.2 ng/ml : M-I = 4.12 ng/ml
- 5 days after Lupron – UL = 1.21 ng/ml : M-I = 0.93 ng/ml
- 7 days after Lupron – UL = 2.20 ng/ml : M-I = 1.60 ng/ml
- 15 days after Lupron – UL = 1.43 ng/ml : M-I = 0.85 ng/ml
- 25 days after Lupron – UL = 2.53 ng/ml : M-I = 1.79 ng/ml
- 29 days after Lupron – UL = 2.12 ng/ml : M-I = 1.74 ng/ml
Table III of this study displays serum M-I levels in another prostate cancer subject over the course of 4 weeks: at week 1 and 2 post-injection the levels were non-detectable, however at week 4 a level of 0.05 ng/ml was noted.
These data appear problematic. What would the levels be 55 days after Lupron?
As mentioned earlier, outside the ‘Metabolism’ section of Lupron Depot’s labels, there is additional pharmacokinetic information.
Under ‘Absorption’ in the 1997 female label,
“a single dose of  3.75 mg was administered by intramuscular injection to healthy female volunteers” (unidentified number).
This study noted
“intact leuprolide and an inactive metabolite could not be distinguished by the assay used in this study”, and leuprolide concentrations “remained relatively stable for about four to five weeks.”
The pediatric and male ‘Absorption’ section in the 1997 Depot labels report “a single [ ] 7.5 mg injection to adult patients” (unidentified number) and again, “intact leuprolide and an inactive major metabolite could not be distinguished by the assay which was employed in the study. Nondetectable leuprolide plasma concentrations have been observed during chronic Lupron Depot 7.5 mg administration .”
And all labels also note that in patients with liver or kidney impairment, the pharmacokinetics of the drug “have not been determined”.
Additional Data for Consideration
Both the 1999 US label and 2017 Canadian monograph for Lupron Depot 3.75 mg and 3-month 11.25 mg (for use in endometriosis) state “a pharmacokinetic study of leuprolide acetate [daily injections] in children has not been performed (p. 28). The initial and subsequent pediatric Depot label does provide trough and mean plasma leuprolide levels that were determined in a subset of 22 children, “indicating no accumulation of leuprolide from repeated administration.”
And curiously, even though Lupron Depot-PED 7.5 mg was approved for use in children in the US, the drug company’s 1998 Lupron Depot label in Australasia (for 7.5 mg and 22.5 mg) states “Use in children: Safety and effectiveness in children have not been established.”
It is also a puzzle how the all labels identify that “diagnostic tests of pituitary gonadotropic and gonadal functions conducted during treatment” and months afterward “may be affected” – when these are the very tests being assayed to ‘monitor’ Lupron’s effects and assess a return to normal function. Moreover, in 1997, the male and pediatric label stated “up to one to two months after discontinuation”, and the female 3.75 mg label stated “up to three months after discontinuation”. And current pediatric labels state “diagnostic tests [ ] conducted during treatment and up to six months after discontinuation of Lupron Depot-PED may be affected.”
Do We Really Know How Lupron is Metabolized?
It would appear we do not. The literature is limited and contradictory at best. One medical text suggests it is “metabolized by enzymes in hypothalamus and anterior pituitary” with a half-life of 3 hours. While another says it is metabolized by being “destroyed within the GI track” with a half-life up to 4.25 hours. Yet another says it has a half-life of up to 6.8 hours. Since first discovered and used in the 1970’s, Lupron has now been injected into humans for almost 50 years. Reports have emerged since its approval suggesting the 3 hour clearance rate is insufficient at best. Adverse event reports show effects lasting for months and years post-injection, indicating either that the clearance is much slower, or more likely, that metabolites continue to circulate and/or store in the body for an indefinite and as yet undetermined time. Early evidence of longer-term adverse effects was known pre-approval in animals and adult populations (examples listed below). The initial (and it is believed only) studies on Lupron’s pharmacological and toxicological data reviewed by the FDA for Lupron’s 1985 approval for palliative treatment of prostate cancer were studies that were approved and submitted by an employee of Lupron’s manufacturer who also is a co-inventor on several patents involving Lupron (i.e., 4,851,211; 4,897,256), the first patent being filed the year after Lupron’s initial FDA approval. In the 1984 FDA documents detailing the toxicological review of these studies, the FDA writes:
“[Rat] testes showed various degrees of testicular degeneration which were detectable within 2 days. The severity of the lesions were greater in testes of rats sacrificed 7 days after cessation of treatment indicating that the effects continued after drug withdrawal (emphasis mine).”
In 1990, an FDA Medical Officer stated:
“[t]he most common adverse event [to Lupron for endometriosis] was hot flashes, the majority of which occurred within 3 months after stop of study [emphasis mine].”
Also related to Lupron’s use in endometriosis in 1990, the Medical Director for Lupron’s manufacturer reported that:
“subclinical but detectable levels of leuprolide have been found in one third of subjects eleven weeks after [the last 3.75 mg] injection.” Why wasn’t this information placed into the 3.75 mg label?
The pediatric daily and depot labels state “immature male rats demonstrated tubular degeneration in the testes even after a recovery period. (emphasis mine)”
In the 2 clinical trials for ‘Lupron + add-back’ for endometriosis,
“five of the 6 increases [in liver enzymes] were observed beyond 6 months of treatment.“
In 1993, the American Hospital Formulary Service stated
“Plasma concentrations of the drug are undetectable in most patients 8 weeks after IM administration of a single dose but may remain detectable for several more weeks in some patients.” (p. 607)
Despite this substantive evidence of continued and lingering effects after drug withdrawal (not to mention the large-scale number of complaints from Lupron victims), there nonetheless appears to be a dismissal from many in the medical community that Lupron could be causing problems after its discontinuation. Many women report their doctors say ‘Lupron would be long gone from your system by now’, etc. Two statements in the medical literature illustrate this point:
In a fertility study using daily Lupron, unexplained data led to the comment that “it seems unlikely that a persistent effect would be found some 64 to 96 half-lives (8 to 12 days) later [p. 877].”
Likewise in a study of Lupron in baboons: “considering the 3-hour half-life for leuprolide acetate, it seems unlikely that the GnRH-a could have any direct effects 1 week later (approximately 56 half-lives) [p. 1071].”
Who Says What About Lupron’s Metabolism?
The 1997 Lupron Depot labels tells us, in ‘Excretion’, that after giving
“3.75 mgs to 3 patients, less than 5% of the dose was recovered as parent and M-I metabolite in the urine.”
And the labels state it is “primarily degraded by peptidase”. But otherwise, the label doesn’t really tell us much.
Medical literature reveals conflicting information. A 1995 ‘Physicians Drug Handbook’ stated both that Leuprolide “is destroyed by the GI tract … [and] the metabolic fate of leuprolide is unclear, but it may be metabolized in the anterior pituitary and hypothalamus“. One 1999 Drug Guide stated Lupron was “metabolized by enzymes in hypothalamus and anterior pituitary“, yet another 1999 drug handbook stated Lupron was “destroyed within the GI tract“.
Lupron is known variously as (among others) an “antineoplastic” and/or “chemotherapy”, and in a 2008 Chemotherapy Source Book, some information on its pharmacokinetics and metabolism is provided: “Metabolism occurs through intravascular and extravascular hydrolysis of the C-terminal amino acids. The drug and peptide fragments are eliminated primarily in the urine, with an elimination half-life of 3 – 4 hours.”
In a 2012 Canadian cancer drug manual, we learn that Lupron’s distribution showed “high concentrations in kidney, liver, pineal, pituitary tissue (and low concentrations in hypothalamus, cerebral cortex, and muscle); and that Lupron is metabolized in the liver, kidney, hypothalamus, pituitary gland [and] no information found [on] active [and] inactive metabolite(s).” I wonder why this information isn’t in Lupron’s labels?
I also wonder why drug information published in 2015 states Lupron’s metabolism and excretion is unknown.
Lupron’s manufacturer tells Americans, through the U.S. Depot-PED’s label, that Lupron-induced
“suppression of ovarian and testicular steroidogenesis [is] reversible on discontinuation of drug therapy”.
Yet, Lupron’s manufacturer tells the consumers of Australia, Belgium, Czech Republic, France, Hungary, Israel, Malaysia, Mexico, Netherlands, New Zealand, Portugal, Russia, South Africa, Singapore, Switzerland, and Turkey (see ‘Lucrin‘ here), through its 2015 foreign label
“No studies in animals or humans have yet established whether this effect is reversible upon discontinuation of drug therapy … [and] [a]n additional mechanism of action, a direct effect on the gonads by downregulation of the gonadotropin receptors, is suggested in some animal studies.”
Where We Are Now
To the best of my knowledge, it does not appear the drug’s metabolism has been properly or even adequately investigated in the pediatric (or adult) population, despite decades of use and decades of patient complaints regarding lingering side effects. Shouldn’t this type of critical information and these parameters be determined before prescribing this molecule to children (or any human)?
After almost 50 years, questions should be answered!
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*Photo: 1994 Lupron Depot Pediatric – Package Insert, PDR
This article was originally published on April 5, 2017.
 AHFS [American Hospital Formulary Service] Drug Information, 1994; p.643.
 Physician’s Desk Reference, Lupron/leuprolide, 1985
 Physician’s Desk Reference, Lupron Depot 3.75 mg.; 1990
 Medical Officer’s Review of Revised Labeling, Submission Dated May 29, 1990, M.D. Review #1. Ragavan, VV. June 7, 1990. NDA [New Drug Application] 20-011.
 Physician’s Desk Reference, Lupron Depot-PED, 7.5 mg, 11.25 mg, 15 mg. 1994
 Memorandum, Division of Biopharmaceutics, November 27, 1984; NDA 19-010.
 Frank, LR; Pharmacokinetics Evaluation Branch I. (“Bioavailability/Bioequivalence Study”, December 20, 1983. NDA 19-010.
 Pharmacokinetics Evaluation Branch, ‘Review of Responses to Deficiencies in a NDA’, Shah, A. May 29, 1987. NDA 19-010
 MIMS Annual 1998, Australasia. 1998. Lupron Depot; p. 9-804.
 Appleton & Lange’s 1999 Drug Guide, p.788.
 Anesthesiology & Critical Care Drug Handbook, 1998-1999. Lexi-Comp Inc, Cleveland. American Pharmaceutical Association; p.491.
 Pharmaceutical Research (1992); 9(2):247.
 Jordan A. FDA Summary Basis of Approval. NDA 19-010. Review and Evaluation of Pharmacology and Toxicology Data. March 1, 1984.
 “Review of Revised Labeling”, April 13, 1990. NDA 20-011. Lupron Depot 3.75 mgs.
 Miller JD. 1990. Leuprolide Acetate for the Treatment of Endometriosis. Current Concepts in Endometriosis: 337.)
 Physicians Drug Handbook, 6th Ed., Springhouse Corp., Springhouse, PN.; p.553.
 Appleton & Lange’s 1999 Drug Guide, Health Professional’s Edition, Stamford CT, Simon & Schuster; p.788.
 Anesthesiology & Critical Care Drug Handbook, 1998-1999. Lexi-Comp Inc, Cleveland. American Pharmaceutical Association; p. 491.