Scott R. Penzak

Pharmacokinetics and Safety of Oral Posaconazole in Neutropenic Stem Cell Transplant Recipients

ABSTRACT The pharmacokinetics of posaconazole oral suspension in neutropenic patients undergoing high-dose chemotherapy and stem cell transplantation were evaluated, and the association of plasma posaconazole exposure with the presence and severity of oral mucositis was explored in this nonrandomized, open-label, parallel-group, multiple-dose pharmacokinetic study. Thirty patients were enrolled and received one of three regimens (group I, 200 mg once daily; group II, 400 mg once daily; group III, 200 mg four times daily) for the duration of neutropenia. The mean total exposure for day 1, as shown by the area under the concentration-time curve from 0 to 24 h (AUC0-24), was 1.96 mg · h/liter in group I and was 51% higher in group II and in group III. Increases in AUC0-24 and maximum plasma concentration (Cmax) in groups II and III were dose related. The AUC0-24 and Cmax values on day 1 were similar between groups II and III. There was interpatient variability of up to 68% in the pharmacokinetic values for our study population. Steady state was attained by days 5 to 6. Average steady-state plasma posaconazole trough values were 192, 219, and 414 ng/ml in groups I, II, and III, respectively. The AUC0-24 and apparent oral clearance increased by increasing dose and dosing frequency. Mucositis appeared to reduce exposure but did not significantly affect mean total posaconazole exposure (AUC and Cmax) at steady state (P = 0.1483). Moreover, this reduction could be overcome by increasing the total dose and dosing frequency. Posaconazole was safe and well tolerated.

Seville (sour) Orange Juice: Synephrine Content and Cardiovascular Effects in Normotensive Adults

The Seville orange extract Citrus aurantium contains m‐synephrine (phenylephrine) and octopamine; it causes cardiac disturbances in animals and is used by humans for weight loss. Juice from the orange (Seville orange juice [SOJ]) is used to “knock out” intestinal cytochrome P450 (CYP) 3A4 in bioavailability studies. The purpose of this study was to determine synephrine and octopamine concentrations in SOJ and SOJs cardiovascular effects in normotensive humans. Subjects consumed 8 ounces of SOJ and water in crossover fashion followed by a repeat ingestion 8 hours later. Hemodynamic (heart rate; systolic, diastolic, and mean arterial pressure) measurements followed. Synephrine and octopamine were determined by high‐performance liquid chromatography. Hemodynamics did not differ significantly between water and SOJ groups. Mean synephrine concentration of SOJ samples was 56.9 ± 0.52 μg/ml; octopamine was not detected. SOJ ingestion by normotensive subjects is expected to be safe. Individuals with severe hypertension, tachyarrhythmias, and narrow‐angle glaucoma and monoamine oxidase inhibitor recipients should avoid SOJ consumption. Persons taking decongestant‐containing cold preparations should also refrain from SOJ intake.

Efavirenz induces CYP2B6-mediated hydroxylation of bupropion in healthy subjects.

Objective:To characterize the effect of efavirenz on bupropion hydroxylation as a marker of cytochrome P450 (CYP) 2B6 activity in healthy subjects. Methods:Thirteen subjects received a single oral dose of bupropion SR 150 mg before and after 2 weeks of efavirenz administration for comparison of bupropion and hydroxybupropion pharmacokinetics. Efavirenz plasma concentrations were also assessed. Subjects were genotyped for CYP2B6 (G516T, C1459T, and A785G), CYP3A4 (A-392G), CYP3A5 (A6986G), and multidrug resistance protein 1 (C3435T). Results:The area under the concentration vs. time curve ratio of hydroxybupropion:bupropion increased 2.3-fold after efavirenz administration (P = 0.0001). Bupropion area under the concentration vs. time curve and Cmax decreased by 55% and 34%, respectively (P < 0.002). None of the CYP2B6 or CYP3A genotypes evaluated were associated with a difference in bupropion or efavirenz clearance. The 2 individuals homozygous for multidrug resistance protein 1 3435-T/T had 2.5- and 1.8-fold greater bupropion and efavirenz clearance, respectively, relative to C/C and C/T individuals (P < 0.05). Conclusions:Our results confirm that efavirenz induces CYP2B6 enzyme activity in vivo, as demonstrated by an increase in bupropion hydroxylation after 2 weeks of efavirenz administration.

Ritonavir decreases the nonrenal clearance of digoxin in healthy volunteers with known MDR1 genotypes.

Our objective was to examine the influence of ritonavir on P-glycoprotein (P-gp) activity in humans by characterizing the effect of ritonavir on the pharmacokinetics of the P-gp substrate digoxin in individuals with known MDR1 genotypes. Healthy volunteers received a single dose of digoxin 0.4 mg orally before and after 14 days of ritonavir 200 mg twice daily. After each digoxin dose blood and urine were collected over 72 hours and analyzed for digoxin. Digoxin pharmacokinetic parameter values were determined using noncompartmental methods. MDR1 genotypes at positions 3435 and 2677 in exons 26 and 21, respectively, were determined using PCR-RFLP analysis. Ritonavir increased the digoxin AUC0–72 from 26.20 ± 8.67 to 31.96 ± 11.24 ng · h/mL (P = 0.03) and the AUC0–8 from 6.25 ± 1.8 to 8.04 ± 2.22 ng · h/mL (P = 0.02) in 12 subjects. Digoxin oral clearance decreased from 149 ± 101 mL/h · kg−1 to 105 ± 57 mL/h · kg−1 (P = 0.04). Other digoxin pharmacokinetic parameter values, including renal clearance, were unaffected by ritonavir. Overall, 75% (9/12) of subjects had higher concentrations of digoxin after ritonavir administration. The majority of subjects were heterozygous at position 3435 (C/T) (6 subjects) and position 2677 (G/T,A) (7 subjects); although data are limited, the effect of ritonavir on digoxin pharmacokinetics appears to occur across all tested MDR1 genotypes. Concomitant low-dose ritonavir reduced the nonrenal clearance of digoxin, thereby increasing its systemic availability. The most likely mechanism for this interaction is ritonavir-associated inhibition of P-gp. Thus, ritonavir can alter the pharmacokinetics of coadministered medications that are P-gp substrates.

Grapefruit juice decreases the systemic availability of itraconazole capsules in healthy volunteers

The systemic availability of itraconazole capsules may be reduced secondary to elevated gastric pH and possibly by presystemic intestinal metabolism via CYP3A4. Grapefruit juice is acidic and an inhibitor of intestinal CYP3A4. To determine the effect of grapefruit juice on the systemic availability of itraconazole capsules, serum itraconazole and hydroxy-itraconazole concentrations were determined in eleven healthy volunteers studied in a randomized, two-way crossover design. Concurrent grapefruit juice resulted in a 43% decrease in the mean itraconazole AUC0-48 (2507 ng x hr/mL versus 1434 ng x hr/mL, p = 0.046) and a 47% decrease in the mean hydroxy-itraconazole AUC0-72 (7264 ng x hr/mL versus 3880 ng x hr/mL, p = 0.025). Grapefruit juice also significantly increased the mean itraconazole Tmax (5.5 versus 4 hours). We conclude that concomitant grapefruit juice does not enhance the systemic availability of itraconazole capsules, but rather appears to impair itraconazole absorption. Therefore, concomitant grapefruit juice will not likely be useful in improving the oral availability of itraconazole capsules.

Echinacea purpurea Significantly Induces Cytochrome P450 3A Activity but Does Not Alter Lopinavir-Ritonavir Exposure in Healthy Subjects

Study Objective. To determine the influence of Echinacea purpurea on the pharmacokinetics of lopinavir‐ritonavir and on cytochrome P450 (CYP)3A and P‐glycoprotein activity by using the probe substrates midazolam and fexofenadine, respectively.

Prednisolone pharmacokinetics in the presence and absence of ritonavir after oral prednisone administration to healthy volunteers.

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.

Influence of ritonavir on olanzapine pharmacokinetics in healthy volunteers.

HIV infection and psychotic illnesses frequently coexist. The atypical antipsychotic olanzapine is metabolized primarily by CYP1A2 and glucuronosyl transferases, both of which are induced by the HIV protease inhibitor ritonavir. The purpose of this study was to determine the effect of ritonavir on the pharmacokinetics of a single dose of olanzapine. Fourteen healthy volunteers (13 men; age range, 20–28 years) participated in this open-label study. Subjects received olanzapine 10 mg and blood samples were collected over a 120-hour post-dose period. Two weeks later, subjects took ritonavir 300 mg twice daily for 3 days, 400 mg twice daily for 4 days, and 500 mg twice daily for 4 days. The next morning, after 11 days of ritonavir, olanzapine 10 mg was administered and blood sampling was repeated. Plasma samples were analyzed for olanzapine with HPLC. We compared olanzapine noncompartmental pharmacokinetic parameter values before and after ritonavir with a paired Student t test. Ritonavir reduced the area under the plasma concentration-time curve of olanzapine from 501 ng · hr/mL (443–582) to 235 ng · hr/mL (197–294) (p < 0.001), the half-life from 32 hours (28–36) to 16 hours (14–18) (p = 0.00001), and the peak concentration from 15 ng/mL (13–19) to 9 ng/mL (8–12) (p = 0.002). Olanzapine oral clearance increased from 20 L/hr (18–23) to 43 L/hr (38–51) (p < 0.001) after ritonavir. Ritonavir significantly reduced the systemic exposure of olanzapine in volunteers. Patients receiving this combination may ultimately require higher olanzapine doses to achieve desired therapeutic effects.

Stenotrophomonas (Xanthomonas) maltophilia: A Multidrug‐Resistant Nosocomial Pathogen

Stenotrophomonas (Xanthomonas) maltophilia is emerging as a multidrug‐resistant nosocomial pathogen. In general, the organism is opportunistic, colonizing or infecting patients with predisposing risk factors such intensive care unit residence, malignancy, mechanical ventilation, and previous antibiotic exposure. It can cause a variety of infections depending on underlying patient‐specific medical conditions. It is often part of multimicrobial infections, and determining its role as a pathogen is difficult. Trimethoprim‐sulfamethoxazole (TMP‐SMX) has traditionally been the most active agent against S. maltophilia. Other classes of antibiotics, with few exceptions, have not been effective. Synergistic antimicrobial combinations are now being investigated due to the bacteriostatic nature of TMP‐SMX, and increasing reports of resistance to TMP‐SMX. The combination of ticarcillinclavulanate plus TMP‐SMX appears to be the most promising regimen studied thus far.

Therapeutic drug monitoring of vancomycin in a morbidly obese patient

The authors describe the therapeutic drug monitoring of vancomycin in a man who is morbidly obese. Because serum vancomycin concentration (SVC) monitoring continues to be deemphasized, nomogram use will likely increase. However, vancomycin dosing nomograms have not been studied in patients who are morbidly obese. Furthermore, in nomograms that incorporate body weight, it is unclear whether ideal or total body weight (IBW and TBW, respectively) should be used to dose the morbidly obese. Therefore, the authors retrospectively evaluated four nomograms (Moellering, Matzke, Lake-Peterson, and Rodvold) and an individualized method in the simulated vancomycin dosing of their patient. Total body weight was more accurate than IBW in selecting a vancomycin dose when using the individualized method and in all nomograms except the Matzke nomogram. The Rodvold nomogram and the individualized method yielded the most appropriate doses. All nomograms suggested dosing intervals that were unacceptably short; the individualized method suggested an appropriately longer interval. Thus, if nomograms or the individualized method are used to empirically dose vancomycin, TBW--not IBW--should be used. Because these nomograms yielded inappropriately short dosing intervals in the patient, it is likely that patients who are morbidly obese represent a unique population in which at least one set of SVCs are necessary to select an appropriate dosing regimen.