Indinavir pharmacokinetics, Therapeutic drug monitoring, Drug-food interactions, Peripheral neuropathies, and Virologic failure.

LV is a 49 year old black male with unknown risk factors for HIV.
  He has no known drug allergies or intolerances to date.

LV has a history of the following opportunistic infections:

• PCP and Oropharyngeal candidiasis.

• HIV+ since April 13,1999 and AIDS since April 23,1999.
• Depression. Anemia. History of seizures

LV was referred for multi-disciplinary discussion because he had been exposed to suboptimal indinavir doses, possibly leading to an increase in his viral load. The patient also complains of tingling and numbness in his feet.

LV began antiretroviral treatment (ARVT) in April of 1999, after being diagnosed with HIV and AIDS following hospitalization for PCP. During the hospitalization, LV was started on his first ARV regimen by a physician unfamiliar with HIV therapies. The regimen consisted of indinavir 200 mg po tid and zidovudine/lamivudine one tablet po bid. LV also experienced seizures while in the hospital and was started on phenytoin.

LV was first seen at the immunodeficiency clinic on 06/04/99. Prior to the visit, his indinavir dose had been increased to 400 mg po tid, and he was taking indinavir with meals. A blood sample was drawn to determine indinavir concentrations. The resulting concentration was lower than expected. Indinavir was subsequently increased to 800 mg po tid and zidovudine/lamivudine was changed to didanosine and stavudine. LV was counseled by the clinical pharmacist on how to appropriately take his ARVT.

LV’s viral load result from 06/04/99 showed a one-log decrease following initiation of ARVT in April of 1999. The follow-up viral load in July of 1999 revealed a one-log increase despite having increased indinavir to the recommended dose of 800 mg po tid and counseling LV on medication adherence and appropriate medication administration. The provider requested an assessment of this case and recommendations for new ARVT.

Current ARVT:

• Indinavir - 800 mg po tid - started 6/4/99
• Stavudine - 30 mg po bid - started 4/27/99
• Didanosine - 300 mg po qd - started 4/27/99

• Indinavir (suboptimal doses)
• Lamivudine
• Zidovudine

• Clarithromycin - 500 mg po qd
• Miconazole - 2% crm top bid
• Paroxetine - 20 mg po qhs
• Sucralfate - 1 gm po qid
• Erythropoeitin - 10,000 u sc tiw
• TMP/SMX - 1 tab po M/W/F
• Phenytoin - 400 mg po qhs
• Multi-vitamin - 1 tab po qd
• Metoclopramide - 10 mg po bid

• LV has very good self-reported adherence with ARVT
• No recent drug or alcohol use.
• Lives at home with parents.
• Works as a grocery store manager.
• His depression is currently being treated with an SSRI
• No children at home.

HIV+, AIDS, anemia, depression, seizure history.

Indinavir Pharmacokinetics

Although there is no clear therapeutic range for indinavir, and pharmacokinetic parameters are highly variable among individuals, LV’s indinavir concentration from 06/04/99 (0.952 uM) was suboptimal when compared to published, full pharmacokinetic profiles of indinavir¹. This suboptimal concentration can be explained by three factors: suboptimal indinavir dosing, taking indinavir with food, and administering indinavir with phenytoin. Initially indinavir was prescribed at a dose of 200 mg po bid for unknown reasons and then increased to 400 mg po bid. The recommended dose is 800 mg po tid. In addition, LV was taking his indinavir with food. Since the drug requires a normal acidic gastric pH (< 3) for optimal absorption, it should be taken on an empty stomach or with a light meal² (toast, black coffee, etc.). Finally, LV was taking phenytoin along with his indinavir. Phenytoin is a potent inducer of the cytochrome P450 3A4 isoenzyme through which indinavir is metabolized. Each of these factors likely contributed to LV’s suboptimal indinavir concentration.

Peripheral Neuropathies

LV also complains of peripheral neuropathies, which are a common side effect of nucleoside therapy such as zidovudine/lamivudine, stavudine and didanosine. Stavudine and didanosine may worsen these neuropathies, therefore the patient should be monitored closely for increased severity. If neuropathies worsen consider discontinuing stavudine and didanosine. It is also reasonable to consider treatment of the neuropathies at this time with amitriptyline or gabapentin^3,4.

Virologic Failure

LV’s one-log increase in viral load is likely secondary to exposure of the virus to suboptimal indinavir concentrations prior to increasing the indinavir dose to 800 mg po tid. This dose may still be suboptimal however, because of the presence of phenytoin. It is possible that virologic resistance developed. At this time, a repeat viral load may be beneficial to confirm the one-log increase. Suboptimal concentrations occurred relatively recently and over a short period of time, therefore consider continuing this ARV regimen and adding ritonavir to improve pharmacokinetic variable s⁵. A second option is changing ARVT in LV. In concordance with recent literature, changing ARVT before the viral load increases to > 50,000 copies/mL, coincides with greater antiviral efficacy⁶. LV’s most recent viral load was 1670 copies/ml.

Patient is feeling better following his recent hospitalization. He reports being very adherent with ARVT and reports no significant barriers to adherence in his life. LV complains of tingling and numbness in his feet although these do not interfere with activities of daily living. He is still able to work without any difficulty.

LV is interested in attending support group sessions. Arrangements are being made at this time. His depression is much improved since starting treatment with paroxetine.

1. Repeat viral load to confirm recent increase
2. Consider adding ritonavir 400 mg po bid to the current ARVT regimen and decreasing indinavir to 800mg bid.
3. Add amitriptyline 25 mg po qhs for peripheral neuropathy and titrate as tolerated

1. Schedule patient for appointment with clinical pharmacist to discuss regimen change and reinforce medication adherence
2. Nurse to call in prescriptions for ritonavir 400 mg bid and indinavir 800 mg po bid.
3. Continue stavudine 30 mg po bid and didanosine 300 mg po qd.
4. Schedule patient for appointment with clinical pharmacist to discuss regimen change and reinforce medication adherences.
5. Draw blood samples at next clinic appointment to measure indinavir and phenytoin concentrations.

1. Acosta EP, Henry K, Baken L, Page LM, Fletcher CV. Indinavir concentrations and antiviral effect. Pharmacotherapy1999;19:708-12. [PubMed]
2. Indinavir package insert. Merck and Co., Inc., 1996, 1997.
3. Dalakas MC, Cupler EJ. Neuropathies in HIV infection. Baillieres Clinical Neurology 1996;5:199-218. [PubMed]
4. Backonja M, Beydoun A, Edwards KR, Schwartz SL, Fonseca V, et.al. Gabapentin for the symptomatic treatment of painful peripheral neuropathy in patients with diabetes mellitus: A Randomized Controlled Trial. JAMA 1998;280:1831-6. [PubMed]
5. Saah A, Winchell G, Seniuk M, Mehrotra D, Deutsch P. Multiple-dose pharmacokinetics (PK) and tolerability of indinavir (IDV) and ritonavir (RTV) combinations in healthy volunteers. 6^th Conference on Retroviruses and Opportunistic Infections 1999 (abstract no. 362).
6. Carpenter CC, Fischl MA, Hammer SM, Hirsch MS, Jacobson DM, et.al. Antiretroviral therapy for HIV infection in 1998: Updated recommendations of the International AIDS Society-USA panal. JAMA 1998;280:78-86. [PubMed]