Pharmacy & Therapeutics - March 2008 - (Page 135) DRUG FORECAST mum plasma concentration (Cmax) of 8.1 to 63 mg/L. The area-under-the-concentration (AUC) time cur ve was determined to be 8.7 to 75.6 mcg • hours/mL. In addition, plasma concentrations after 11 doses of 500 mg were reported with no significant differences. Mean Cmax, halflife, and the AUC after one dose and 11 doses of 500 mg were 35 versus 32 mcg/ mL, 0.93 versus 93 hours, and 40.2 versus 35.2 mcg • hours/mL, respectively. These data represent an average half-life of one hour, with multiple dosing thus required over a 24-hour period. As stated earlier, doripenem is minimally protein-bound (average binding, 8.1%). At steady state, the median volume of distribution is 16.8 liters. The concentration of doripenem in the peritoneal and retroperitoneal fluid equals or exceeds concentrations required to inhibit most susceptible bacteria. Doripenem does not undergo hepatic metabolism and is thus not expected to be affected by hepatic impairment. It is metabolized to an inactive metabolite, doripenem-M1 by the enzyme, DHP-1. Doripenem is cleared by the kidneys at a mean clearance rate of 10.8 L/hour, 15% of its metabolite is excreted through glomerular filtration and tubular se cretion, and 70% of the drug is excreted unchanged. The clearance rate is slightly higher in patients of Hispanic and Latino descent than in those of Caucasian descent. No differences were seen among patients of other racial or ethnic backgrounds. Over a four-hour hemodialysis session, the total recovered doripenem dose after dialysis was reduced by 52%. A 500-mg dose given one hour before hemodialysis yielded 231 mg of doripenem and 28 mg of the inactive metabolite. Although the hemodializability of doripenem has been determined, there is no current recommendation for dosage adjustments in patients undergoing hemodialysis. total of 946 adults with complicated intraabdominal infections received either IV doripenem 500 mg every eight hours, given over one hour, or IV meropenem 1 g every eight hours, given over three to five minutes. After a minimum of three days of IV treatment, patients in both arms were allowed to switch to an oral regimen of amoxicillin/clavulanate (Augmentin, GlaxoSmithKline) 875 mg/ 125 mg twice daily for a total of five to 14 days of therapy. As for clinical cure rates among microbiologically evaluable patients, dori penem was determined to be non-inferior to meropenem at 25 to 45 days at the end of treatment. In one study, the doripenem clinical cure rate was 82.8% and the meropenem rate was 85.9%. In the second study, the doripenem rate was 81% and the meropenem rate was 82.1%. Noninferiority was also observed among the microbiological modified intent-to-treat patients, which included those with pathogen isolation at the baseline evaluation without regard to susceptibility. Nosocomial Pneumonia9 A New Drug Application (NDA) for doripenem is currently under review by the FDA for the additional indication of nosocomial pneumonia, based on two international multicenter, randomized, open-label, comparison phase 3 clinical trials. In one study, 448 adults were enrolled and were randomly assigned to receive a treatment regimen of IV doripenem 500 mg every eight hours, given over one hour, or IV piperacillin/tazobactam 4.5 g every six hours. All patients had clinically and radiologically confirmed nosocomial pneumonia, including earlyonset ventilator-associated pneumonia, reported within the first five days of ventilation onset. (Early onset was considered less than five days of mechanical ventilation.) After a minimum of three days of IV therapy, all patients were allowed to switch to oral levofloxacin 750 mg once daily for seven to 14 days of treatment. Adjunctive antipseudomonal therapy was initiated in about 80% of clinically evaluable patients. In the other study, 525 adults were enrolled and were randomly assigned to receive either IV doripenem 500 mg every eight hours, given over four hours; IV imipenem/cilastatin 500 mg; or 1 g every six or eight hours. All patients had clinically and radiologically confirmed nosocomial pneumonia, including earlyonset and late-onset ventilator-associated pneumonia. (Late onset was considered five days or more of mechanical ventilation.) After a minimum of three days of IV therapy, all patients were allowed to switch to oral levofloxacin 750 mg once daily for seven to 14 days of treatment. Adjunctive antipseudomonal therapy was initiated in about 22% of clinically evaluable patients. As for clinical cure rates among clinically evaluable patients, doripenem was found to be non-inferior to piperacillin/ tazobactam and imipenem/cilastatin at six to 20 days after the completion of treatment in both studies (81.3% vs. 79.8% and 68.3% vs. 64.8%, respectively). Noninferiority was also observed in the clinical modified intent-to-treat patients. Complicated Urinary Tract Infections7,9 In two multinational multicenter, randomized double-blind studies, a total of 1,171 adults with complicated UTIs, including pyelonephritis, were evaluated. In one study, the authors compared IV doripenem 500 mg every eight hours, given over one hour, with IV levofloxacin (Levaquin, PriCara) 250 mg once daily. In the other study, the methodology was the same but was not comparative. In both studies, all patients were allowed to switch to an oral levofloxacin regimen of 250 mg once daily for a total of 10 days of therapy. Oral or IV levofloxacin 500 mg once daily for 10 to 14 days was also given to patients with confirmed concurrent bacteremia. In terms of overall microbiological cure rates, doripenem was considered to be non-inferior to meropenem among patients who were microbiologically evaluable at five to 11 days at the end of therapy. Eradication rates were 82.1% with doripenem and 83.4% with meropenem. Non-inferiority was also observed among microbiological modified intent-to-treat population, which included patients with pretreatment urine cultures. CLINICAL TRIALS The FDA’s approval of doripenem was based on four international prospective, multicenter, non-inferiority studies. Complicated Intra-abdominal Infections7,9 In two identical multinational multicenter, randomized, double-blind studies, a Vol. 33 No. 3 • March 2008 • P&T® 135
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