Increased aripiprazole concentrations in an HIV-positive male concurrently taking duloxetine, darunavir, and ritonavir.
OBJECTIVE
To report a case of increased aripiprazole concentrations during coadministration with darunavir, ritonavir, and duloxetine.


METHODS
A 43-year-old HIV-positive Hispanic man received darunavir/ritonavir-based antiretroviral therapy (ART) in addition to aripiprazole and duloxetine for depression and anxiety. A month after the aripiprazole dosage was increased to 50 mg daily, the patient developed confusion and loss of coordination. Weeks later, he presented to the emergency department with fever, cough, headache, neck stiffness, back pain, and blurred vision and was admitted for possible meningitis. Because symptoms improved with pain control and intravenous fluids during hospitalization, he was discharged within a couple days after admission. One month later he was readmitted for worsening symptoms, and the resulting diagnostic workup showed unremarkable findings except for lymphadenopathy (LAD). This finding was attributed to discontinuing ARTs after his first admission. He was discharged on aripiprazole 50 mg daily, darunavir 800 mg daily, ritonavir 100 mg daily, and duloxetine 60 mg daily. A random steady-state concentration of aripiprazole was 1100 ng/mL (therapeutic concentration 100-200 ng/mL) obtained 49 days after discharge.


CONCLUSIONS
The Horn Drug Interaction Probability Scale demonstrated a possible relationship between the increased aripiprazole concentration and coadministration of darunavir/ritonavir and duloxetine, which inhibit CYP3A4 and 2D6. Potential confounders to the increased concentration include duloxetine inhibition of CYP2D6 polymorphism, possible 2D6 polymorphism, and exceeding aripiprazole's maximum dose. The initial presentation of confusion and loss of coordination may have been early signs of aripiprazole toxicity, which relapsed as shown by his symptoms prior to admission.


CONCLUSIONS
The interaction between aripiprazole and darunavir, ritonavir, and duloxetine may be significant. Clinicians should be cognizant of increased risk of aripiprazole toxicity in HIV-positive patients concurrently taking ritonavir-boosted ART and other cytochrome P450 inhibitors like duloxetine. Dose adjustments or monitoring parameters should be an area of research and discussion.
Santa Clara Valley Medical Center, PACE Clinic, San Jose, CA, USA.
Gregory L
GL
Aung
John G
JG
O'Brien
Pamela G
PG
Tien
Laura S
LS
Kawamoto
D000328:Adult; D000928:Antidepressive Agents / Q000494:pharmacology; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology; D001007:Anxiety / Q000188:drug therapy; D000068180:Aripiprazole; D065607:Cytochrome P-450 Enzyme Inhibitors; D000069454:Darunavir; D003863:Depression / Q000188:drug therapy; D004305:Dose-Response Relationship, Drug; D000068736:Duloxetine Hydrochloride; D015658:HIV Infections / Q000188:drug therapy; D017320:HIV Protease Inhibitors / Q000494:pharmacology; D006801:Humans; D008297:Male; D010879:Piperazines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D015363:Quinolones / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D019438:Ritonavir / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology*; D013876:Thiophenes / Q000494:pharmacology*
D000928:Antidepressive Agents; D014150:Antipsychotic Agents; D065607:Cytochrome P-450 Enzyme Inhibitors; D017320:HIV Protease Inhibitors; D010879:Piperazines; D015363:Quinolones; D013449:Sulfonamides; D013876:Thiophenes; D000068180:Aripiprazole; D000068736:Duloxetine Hydrochloride; D019438:Ritonavir; D000069454:Darunavir