Prednisolone Pharmacokinetics
Prednisolone Pharmacokinetics
Corticosteroid therapy has been associated with bone toxicities (eg, osteonecrosis) and Cushing syndrome in HIV-infected patients; this may be partially attributable to a pharmacokinetic drug interaction between HIV protease inhibitors and corticosteroids. The purpose of this study was to characterize the influence of low-dose ritonavir on prednisolone pharmacokinetics in healthy subjects. Ten HIV-seronegative volunteers were given single oral doses of prednisone, 20 mg, before (baseline) and after receiving ritonavir, 200 mg, twice daily for 4 and 14 days. After each prednisone dose, serial blood samples were collected and prednisolone concentrations were determined; pharmacokinetic parameter values were compared between the groups. Geometric mean ratios (GMRs, 90% confidence interval [CI]) of the prednisolone area under the plasma concentration versus time curve (AUC0-∞) after 4 and 14 days of ritonavir versus baseline were 1.41 (90% CI: 1.08 to 1.74) and 1.30 (90% CI: 1.09 to 1.49), respectively (P = 0.002 and P = 0.004, respectively). GMRs of prednisolone apparent oral clearance (Cl/F) were 0.71 (09% CI: 0.57 to 0.93) and 0.77 (90% CI: 0.67 to 0.92) after 4 and 14 days of ritonavir versus baseline, respectively (P = 0.0004 and P = 0.0003, respectively). Ritonavir significantly increased the systemic exposure of prednisolone in healthy subjects. Results from this investigation suggest that corticosteroid exposure is likely elevated in HIV-infected patients receiving protease inhibitors.
Potent combination antiretroviral therapy has been shown to reduce morbidity and mortality in patients with HIV infection. Nonetheless, drug interactions and toxicities continue to complicate the pharmacologic management of HIV infection. Patients with HIV infection typically receive at least 3 to 4 antiretroviral medications in addition to other drugs for the treatment of concurrent medical conditions, supportive care, prophylaxis or treatment of opportunistic infections, and immunomodulation. Several of these conditions such as asthma, inflammatory arthritis, neoplastic diseases, and renal or liver transplantation are routinely treated with drug regimens that include systemic corticosteroids (eg, prednisone).
Corticosteroid administration has been associated with a variety of toxicities in patients with HIV infection. There are multiple reports of iatrogenic Cushing syndrome in patients with HIV infection who were receiving fluticasone (oral and nasal inhalation dosage forms) in combination with the HIV protease inhibitor ritonavir. These reports are consistent with results from a recent investigation in volunteers in which fluticasone propionate aqueous nasal spray (200 µg administered once daily) in combination with ritonavir (100 mg administered twice daily for 7 days) resulted in significant increases in plasma fluticasone concentrations and a marked decrease (86%) in the plasma cortisol area under the plasma concentration versus time curve (AUC).
Several studies have also identified corticosteroid use as a potential risk factor for the development of osteonecrosis of the femoral head in patients with HIV infection. Of note, many of the patients in these investigations were on concurrent protease inhibitor-containing antiretroviral regimens, leading to speculation that protease inhibitors may impair the cytochrome P450 (CYP) 3A4-mediated metabolism of corticosteroids, thereby increasing their systemic exposure and toxicity potential. Indeed, other CYP3A4 inhibitors such as certain azole antifungals and diltiazem have been shown to elevate prednisolone concentrations in healthy volunteers administered single doses of prednisone (which is rapidly converted to prednisolone in vivo). These data suggest that medications that inhibit CYP3A4 (eg, all available HIV protease inhibitors) may increase the systemic exposure and toxicity potential of prednisolone.
The purpose of this study was to characterize the influence of the HIV protease inhibitor ritonavir on prednisolone pharmacokinetics in healthy volunteers receiving single oral doses of prednisone before and on days 4 and 14 of a 2-week course of ritonavir administration.
Corticosteroid therapy has been associated with bone toxicities (eg, osteonecrosis) and Cushing syndrome in HIV-infected patients; this may be partially attributable to a pharmacokinetic drug interaction between HIV protease inhibitors and corticosteroids. The purpose of this study was to characterize the influence of low-dose ritonavir on prednisolone pharmacokinetics in healthy subjects. Ten HIV-seronegative volunteers were given single oral doses of prednisone, 20 mg, before (baseline) and after receiving ritonavir, 200 mg, twice daily for 4 and 14 days. After each prednisone dose, serial blood samples were collected and prednisolone concentrations were determined; pharmacokinetic parameter values were compared between the groups. Geometric mean ratios (GMRs, 90% confidence interval [CI]) of the prednisolone area under the plasma concentration versus time curve (AUC0-∞) after 4 and 14 days of ritonavir versus baseline were 1.41 (90% CI: 1.08 to 1.74) and 1.30 (90% CI: 1.09 to 1.49), respectively (P = 0.002 and P = 0.004, respectively). GMRs of prednisolone apparent oral clearance (Cl/F) were 0.71 (09% CI: 0.57 to 0.93) and 0.77 (90% CI: 0.67 to 0.92) after 4 and 14 days of ritonavir versus baseline, respectively (P = 0.0004 and P = 0.0003, respectively). Ritonavir significantly increased the systemic exposure of prednisolone in healthy subjects. Results from this investigation suggest that corticosteroid exposure is likely elevated in HIV-infected patients receiving protease inhibitors.
Potent combination antiretroviral therapy has been shown to reduce morbidity and mortality in patients with HIV infection. Nonetheless, drug interactions and toxicities continue to complicate the pharmacologic management of HIV infection. Patients with HIV infection typically receive at least 3 to 4 antiretroviral medications in addition to other drugs for the treatment of concurrent medical conditions, supportive care, prophylaxis or treatment of opportunistic infections, and immunomodulation. Several of these conditions such as asthma, inflammatory arthritis, neoplastic diseases, and renal or liver transplantation are routinely treated with drug regimens that include systemic corticosteroids (eg, prednisone).
Corticosteroid administration has been associated with a variety of toxicities in patients with HIV infection. There are multiple reports of iatrogenic Cushing syndrome in patients with HIV infection who were receiving fluticasone (oral and nasal inhalation dosage forms) in combination with the HIV protease inhibitor ritonavir. These reports are consistent with results from a recent investigation in volunteers in which fluticasone propionate aqueous nasal spray (200 µg administered once daily) in combination with ritonavir (100 mg administered twice daily for 7 days) resulted in significant increases in plasma fluticasone concentrations and a marked decrease (86%) in the plasma cortisol area under the plasma concentration versus time curve (AUC).
Several studies have also identified corticosteroid use as a potential risk factor for the development of osteonecrosis of the femoral head in patients with HIV infection. Of note, many of the patients in these investigations were on concurrent protease inhibitor-containing antiretroviral regimens, leading to speculation that protease inhibitors may impair the cytochrome P450 (CYP) 3A4-mediated metabolism of corticosteroids, thereby increasing their systemic exposure and toxicity potential. Indeed, other CYP3A4 inhibitors such as certain azole antifungals and diltiazem have been shown to elevate prednisolone concentrations in healthy volunteers administered single doses of prednisone (which is rapidly converted to prednisolone in vivo). These data suggest that medications that inhibit CYP3A4 (eg, all available HIV protease inhibitors) may increase the systemic exposure and toxicity potential of prednisolone.
The purpose of this study was to characterize the influence of the HIV protease inhibitor ritonavir on prednisolone pharmacokinetics in healthy volunteers receiving single oral doses of prednisone before and on days 4 and 14 of a 2-week course of ritonavir administration.