PK Data on Investigational HIV Protease Inhibitor 433908

Newswise — At A Glance

* These PK data suggest that 908 can be co-administered without dose adjustments or dose separation with Maalox TC or Zantac (antacids) by HIV/AIDS patients suffering from heartburn or other gastrointestinal problems.

* Co-administration of 908 with Lipitor (ATO) did not significantly affect the PK of 908 but ATO exposure was considerably increased, as expected.

Pharmacokinetic (PK) data from two clinical studies of the investigational HIV protease inhibitor (PI) 433908 (908) were presented here today at the 43rd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC). The studies were conducted to evaluate the interactions of 908 with medications commonly used for heartburn and lipid disorders. Results from the first study indicate that 908 can be co-administered with the antacids Maalox TC or Zantac® (ranitidine HCL). In a second study, results demonstrate that co-administration of 908 with the cholesterol-lowering drug Lipitor (ATO), did not significantly affect the PK of 908, but ATO exposure was considerably increased as expected.

908 is currently under review by the Food and Drug Administration following submission of data by GlaxoSmithKline from three pivotal Phase III clinical trials studying the safety and efficacy of the drug. The compound was co-discovered by GSK and Vertex Pharmaceuticals Incorporated (NASDAQ: VRTX).

"These data provide further information about the use of 908, which is currently under review by the FDA as an HIV protease inhibitor dosed once daily (when boosted with ritonavir) or twice daily (boosted or unboosted). 908 is designed to be dosed in four tablets per day, with no food or water restrictions," said Doug Manion, M.D., vice president of clinical development and medical affairs for GSK.

908 Co-administered with Maalox TC or Zantac "It is common for HIV patients to take antacids or other medications to alleviate heartburn or other gastrointestinal problems: therefore, it is important to assess whether a new drug interacts with these commonly administered therapies," said Susan Ford, clinical pharmacokineticist for GSK and lead author of poster A-1606 presented at ICAAC. "These pharmacokinetic data suggest that 908 can be co-administered with Maalox TC or Zantac without dose adjustments or separation of dosing."

In the crossover study, 26 healthy volunteers completed three treatments: 1,400 mg of 908; 1,400 mg of 908 immediately following ingestion of 30 mL of Maalox TC; and 1,400 mg of 908 one hour after taking 300 mg of Zantac. The treatments were separated by four to seven days to be certain that previously taken drugs were no longer present in the body.

When dosed in combination with 908, Maalox TC and Zantac decreased plasma APV AUC by 18 percent and 30 percent, respectively. Plasma C12 concentrations of APV were unaffected by Maalox TC or Zantac.

908 co-administered with Lipitor (atorvastatin) In a second study, (poster A-1622), researchers found that plasma concentrations of the cholesterol lowering drug atorvastatin (ATO), a HMG-CoA reductase inhibitor, or "statin," were significantly increased when ATO was co-administered with 908 or 908/ritonavir (908/r), but ATO had no significant effect on the PK of APV. Statins are frequently prescribed in the HIV population to counteract disturbances in lipid metabolism that occur in many patients being treated with antiretroviral therapy.

"These data suggest that ATO doses should not exceed 20 mg per day when co-administered with 908 or 908/r, but once approved, the prescribing information for 908 will provide the most up-to-date information on potential drug interactions," said Mary Beth Wire, clinical pharmacokineticist for GSK and lead author of poster A-1622 presented at ICAAC.

In the study, 39 healthy adults were enrolled and 26 subjects completed the study. The volunteers were given ATO 10 mg once daily for four days followed by a seven- to ten-day washout period. Next, volunteers received 1,400 mg of 908 twice daily, or 700 mg of 908 combined with 100 mg of ritonavir (RTV) twice daily for 14 days. Finally, all volunteers received 908 or 908/r twice daily in combination with 10 mg ATO once daily.

Plasma ATO AUC increased 2.3-fold and Cmax increased 4-fold in combination with 1,400 mg 908 twice daily. Plasma ATO AUC increased 2.5-fold and Cmax increased 2.8-fold in combination with 700 mg 908 plus 100 mg RTV twice daily.

GlaxoSmithKline is one of the world's leading research-based pharmaceutical and healthcare companies and an industry leader in HIV research and therapies. The company is engaged in basic research programs designed to investigate new targets to treat HIV.

Maalox TC is a registered trademark of Novartis AG.Zantac is a registered trademark of the GlaxoSmithKline Group of Companies.Lipitor is a registered trademark of Pfizer, Inc.