Priapism Induced by Boceprevir-CYP3A4 Inhibition and α-Adrenergic Blockade: Case Report

A 44 year-old Caucasian male presented to the emergency department with a three day history of priapism requiring a surgically performed distal penile shunt. A drug-drug interaction is the suspected cause whereby CYP3A4 inhibition by boceprevir led to increased exposures of doxazosin, tamsulosin and/or quetiapine, resulting in additional α-adrenergic blockade.

Abstract

A 44-year-old white man presented to the emergency department with a 3-day history of priapism requiring a surgically performed distal penile shunt. A drug–drug interaction is the suspected cause whereby CYP3A4 inhibition by boceprevir led to increased exposures of doxazosin, tamsulosin, and/or quetiapine, resulting in additional α-adrenergic blockade.

A 44-year-old white male presented to the emergency department with a 3-day history of priapism. The patient's comorbidities included human immunodeficiency virus (HIV) with an undetectable viral load and stable CD4 count of 1066 cells/µL (26%), hepatitis C virus (HCV) genotype 1a with a FibroSURE result of 0.18 (indicating no fibrosis), benign prostatic hyperplasia (BPH), hypertension, mood disorder, gastroesophageal reflux disease, musculoskeletal neck pain, occasional diarrhea, and a recent episode of bronchitis. The patient reported no previous history of priapism. His concomitant medications (Table 1) included efavirenz 600 mg/emtricitabine 200 mg/tenofovir disoproxil 300 mg by mouth daily, boceprevir 800 mg 3 times daily, peginterferon alfa-2b 120 µg subcutaneously every 7 days, ribavirin 400 mg every morning and 600 mg every evening, doxazosin 8 mg at bedtime, tamsulosin 0.4 mg daily, 1–3 tablets of quetiapine 100 mg every evening, testosterone cypionate 200 mg intramuscularly every 14 days for hypogonadism (free testosterone = 11.9 ng/dL, total testosterone = 540 ng/dL evaluated 21 months prior to priapism), ondansetron 4 mg every 6 hours for nausea, esomeprazole 40 mg daily, lithium 1200 mg at bedtime (0.8 mmol/L; 3 weeks postincident), losartan 50 mg daily, naproxen 500 mg twice daily as needed for pain, acetaminophen/oxycodone 5–325 mg every 6 hours as needed for pain, loperamide 2 mg as needed for diarrhea, codeine/guaifenesin 15 mg/5 mL–10 mL 4 times daily as needed for cough, and cyclobenzaprine 10 mg every 8 hours as needed for muscle spasms. Nine days prior to developing priapism, the patient initiated boceprevir following a 4-week lead-in with peginterferon alfa and ribavirin for HCV treatment. Other than the above prescription and over-the-counter medications, the patient denied taking any herbal or vitamin supplements or phosphodiesterase inhibitors prior to developing priapism. The patient did take pseudoephedrine at home to attempt to alleviate symptoms with no resolution prior to presenting to the emergency department.

Table 1.

Drug Interaction Between Patient's Medication List and Boceprevir

Medication	Route of Metabolism	Interaction Potential	Priapism Documented
Efavirenz/emtricitabine/tenofovir	CYP3A, 2B6	Efavirenz decreases boceprevir plasma trough concentrations [1]	No
Doxazosin	CYP3A, 2D6, and 2C19	Boceprevir may increase doxazosin concentrations through CYP3A inhibition	Yes
Tamsulosin	CYP3A4, 2D6	Boceprevir may increase tamsulosin concentrations through CYP3A inhibition	Yes
Quetiapine	CYP3A4	Boceprevir may increase quetiapine concentrations through CYP3A inhibition	Yes
Esomeprazole	CYP2C19, 3A4	None expected [2]	No
Lithium	Renal	None expected	No
Losartan	CYP2C9, 3A4	Boceprevir may increase losartan concentrations through CYP3A inhibition [3]	No
Naproxen	Extensively metabolized by the liver to 6-O-desmethyl naproxen [4]	None expected	No
Acetaminophen/oxycodone	CYP3A4 and 2D6	Boceprevir may increase oxycodone concentrations through CYP3A inhibition	No
Loperamide	CYP3A4 [5]	Boceprevir may increase loperamide concentrations through CYP3A inhibition	No
Codeine/guaifenesin	CYP2D6, 3A4, and UDP-glucuronosyltransferase 2B7 and 2B4	Boceprevir may increase codeine concentrations through CYP3A inhibition	No
Cyclobenzaprine	CYP3A4, 1A2, and 2D6 [6]	Boceprevir may increase cyclobenzaprine concentrations through CYP3A inhibition	No
Testosterone cypionate	Metabolized to dihydrotestosterone and estradiol by steroid 5 reductase and an aromatase enzyme complex, respectively [7]	None expected	No, but can assist in treating erectile dysfunction [8]
Ondansetron	Hepatic oxidative metabolism to 7-hydroxy or 8-hydroxyondansetron [9]	None expected	No

In the emergency department, unsuccessful attempts were made to irrigate and inject with phenylephrine to achieve detumescence. As detumescence was not achieved, a distal penile shunt was surgically performed. Among the multitude of medications that the patient was taking (Table 1), it was thought that a drug–drug interaction between boceprevir and doxazosin, tamsulosin, and/or quetiapine were the cause of priapism. As such, doxazosin and tamsulosin were discontinued postoperatively. Additionally, the patient experienced excessive nausea and vomiting while on boceprevir, despite being treated with ondansetron 4 mg 3 times daily, ultimately leading to discontinuation of HCV treatment. The patient remained on quetiapine for treatment of his mood disorder. In the 2 months since the procedure, there has been no recurrence of priapism. The patient's penile sensitivity has returned, and sexual function is slowly improving, though it is not yet back to baseline.

DISCUSSION

Boceprevir is an NS3/4A hepatitis C virus (HCV) protease inhibitor, used in combination with peginterferon and ribavirin to treat HCV [10]. This 3-drug combination has yielded cure rates of approximately 66% compared to the cure rate of 38% with peginterferon and ribavirin alone; thus, peginterferon, ribavirin, and an HCV protease inhibitor (boceprevir or telaprevir) are now the standard of care for HCV genotype 1. Boceprevir undergoes metabolism through aldoketoreductase and CYP3A4/5 [10]. Boceprevir is also a moderate CYP3A inhibitor and weak inhibitor of P-glycoprotein [11]. Boceprevir shows weak to no inhibition of organic anion transporting polypeptide 1B1, breast cancer resistance protein, and multidrug resistance protein 2 [11].

Doxazosin is a nonselective α-1 adrenergic antagonist used to treat BPH and/or hypertension. Tamsulosin is an uroselective α-1a adrenergic antagonist used to treat BPH. Simultaneous use of tamsulosin and doxazosin for BPH is unusual. Both doxazosin and tamsulosin are metabolized by CYP3A4 and both have documented case reports of priapism associated with their use [12–16]. The case reports range from 32- to 66-year-old men either on doxazosin 4 mg daily or tamsulosin 0.4 mg daily. Priapism occurred anywhere between immediately after the first dose to 15 days after starting therapy. Our patient had been taking doxazosin and tamsulosin for 10 months and 2 years, respectively. Herbal products, supplements, and phosphodiesterase inhibitors were not reported as being used. The only concomitant medication reported was hydrochlorothiazide in 1 case report.

Quetiapine is an antipsychotic that antagonizes multiple receptors including serotonin 5HT1a and 5HT2, dopamine D1 and D2, histamine H1, and adrenergic α-1 and α-2 receptors. Quetiapine relies solely on CYP3A for metabolism, and the potent CYP3A inhibitor ketoconazole increases quetiapine exposures by 335%. This suggests that boceprevir may significantly increase concentrations of quetiapine as well. Multiple case reports have linked quetiapine with priapism through α-1 adrenergic receptor antagonism [17–25]. The case reports involve male patients ranging from 21 to 50 years of age on variable quetiapine doses (25–800 mg total daily dose); priapism occurred anywhere between 2 and 8 days after starting quetiapine therapy or following a dose change in quetiapine. Our patient had been taking quetiapine for 2 years. Several of the case reports show concomitant medications including escitalopram, zolpidem, lamivudine/zidovudine, nevirapine, lopinavir/ritonavir, and pantoprazole.

Priapism associated with tamsulosin, doxazosin, and quetiapine may be concentration dependent as observed in a case report in which an individual was stable on 4 mg of doxazosin for 1 year, but had taken an 8-mg dose 15 days prior to presentation of priapism [12]. The mechanism of priapism involving these 3 medications revolves around their action on adrenergic nerves. Adrenergic nerves are present in cavernosal and helicine arteries, and the cavernosal smooth muscle. Stimulation of the adrenergic nerves by norepinephrine allows for contraction of the smooth muscle and detumescence [12]. Blockade of the α-adrenoceptors shifts the vascular equilibrium into the direction of prolonged erection by directly inhibiting the sympathetic impulse of detumescence [12].

Although the product labeling does not state that boceprevir has a drug interaction with α antagonists or quetiapine, it is likely that boceprevir's inhibition of the enzyme CYP3A4 led to increased concentrations of doxazosin, tamsulosin, and/or quetiapine. These elevated concentrations then likely resulted in increased inhibition of α-adrenergic receptors leading to priapism in our patient. A similar incident was observed in a case report involving a 50-year-old man on lopinavir/ritonavir, also a CYP3A4 inhibitor, which led to priapism hours after starting quetiapine [21].

Testosterone cypionate has no effect on α-adrenergic receptors, and its concentrations are unlikely to be raised by an interaction with boceprevir. However, testosterone cypionate does have the benefit of giving men erections if they have had difficulties due to HIV-induced hypogonadism. Unfortunately, our patient's current testosterone levels were not available, but previous measurements did not show supraphysiologic levels. Testosterone cypionate's contribution to priapism in this case cannot be ruled out, and will be classified as a contributing factor.

It is unlikely that this patient's priapism was a side effect of HCV treatment. The preponderance of evidence suggests this was the result of a drug–drug interaction. As shown in Table 1, there is no pharmacologic rationale to suspect any of the patient's other concomitant medications as contributing to the priapism, and no documented cases of priapism with these other medications. The patient also denies taking excessive doses of any of his medications. Boceprevir and efavirenz are not recommended to be coadministered based on a healthy volunteer study that showed a 44% decrease in boceprevir trough concentrations [10]; however, the patient was participating in a research study that allowed the use of efavirenz with boceprevir.

To the best of our knowledge, this is the first published case report of priapism resulting from a drug–drug interaction between boceprevir and doxazosin, tamsulosin, and/or quetiapine. Our analysis is limited as we were not able to obtain a blood sample from the patient for confirmatory pharmacokinetic analysis. Our case was submitted to the Food and Drug Administration's MedWatch program, and we advocate for an additional warning that α-antagonists not be used concomitantly with boceprevir. Additionally, avoidance of quetiapine and use of an alternative antipsychotic is advised during boceprevir treatment.

In conclusion, our patient's priapism was most likely the result of boceprevir's inhibition of doxazosin, tamsulosin, and/or quetiapine's metabolism through CYP3A4. Additionally, testosterone cypionate may have played a contributing role independent of the drug–drug interaction. With future use of boceprevir, the drug–drug interactions as noted above should be a consideration when choosing medications to treat BPH.