Comparison of Atovaquone (566C80) with Trimethoprim-Sulfamethoxazole to Treat Pneumocystis carinii Pneumonia in Patients with AIDS

Hughes, W. William; Leoung, Gifford G.; Kramer, Françoise; Bozzette, Samuel S.A.; Safrin, Sharon; Frame, Peter; Clumeck, Nathan; Masur, Henry; Lancaster, D; Chan, C. Y.; Lavelle, James J.; Rosenstock, Joel J.; Falloon, Judith; Feinberg, Judith; Lafon, Steve; Rogers, Michael M.; Sattler, Fred F.

doi:10.1056/nejm199305273282103

Cited by 281 publications

(147 citation statements)

References 11 publications

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“…14,[16][17][18] Hematologic toxicity was uncommon. 17 Atovaquone tablets, used in earlier studies, have been discontinued due to poor bioavailability.…”

Section: Discussionmentioning

confidence: 99%

“…Although pharmacokinetic studies have shown a direct correlation between efficacy and the steady-state plasma concentration, 16 steady-state plasma atovaquone concentrations were not studied in the study population. However, in a small series of solid organ transplant patients at this center adequate atovaquone serum levels (levels exceeding the MIC for P. carinii) were achieved after a prophylactic dosing regimen of 1500 mg daily of atovaquone.…”

Section: Discussionmentioning

confidence: 99%

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A prospective randomized trial comparing the toxicity and safety of atovaquone with trimethoprim/sulfamethoxazole as Pneumocystis carinii pneumonia prophylaxis following autologous peripheral blood stem cell transplantation

Colby

McAfee

Sackstein

et al. 1999

Bone Marrow Transplant

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Summary:Pneumonia due to Pneumocystis carinii is an infrequent complication following autologous stem cell transplantation (ASCT) which is associated with a high mortality. Although administration of trimethoprim/sulfamethoxazole (TMP/SMX) is an effective prophylactic strategy for Pneumocystis carinii pneumonia (PCP), treatment-associated toxicity frequently results in discontinuation of therapy. We have conducted a prospective randomized trial comparing atovaquone, a new anti-Pneumocystis agent, with TMP/SMX for PCP prophylaxis following autologous peripheral blood stem cell (PBSC) transplantation. Thirty-nine patients were studied. Twenty patients received atovaquone suspension and 19 patients received TMP/SMX. The median ages were 44 (range 20-68) and 47 (range 32-63) years, respectively. A similar number of patients with solid tumors (14 vs 15) and hematologic malignancies (five vs five) were treated in each group. Either TMP/SMX (160/800 mg) or atovaquone (1500 mg) was administered daily from transplant day −5 until day −1, discontinued from day 0 to engraftment, then resumed 3 days per week until day +100 post-transplant. The median time to engraftment (ANC Ͼ0.5 × 10 9 /l) was similar in both groups. Eighty percent of the patients randomized to atovaquone prophylaxis completed the study. Four atovaquone-treated patients were removed from study; two patients (10%) did not receive a transplant and two patients (10%) were removed due to a protocol violation. None of the 16 patients treated with atovaquone experienced treatment-associated adverse effects. Of the 19 patients randomized to receive TMP/SMX, 55% completed the study. Nine TMP/SMX-treated patients were removed from the study; one patient (5%) did not receive a transplant and eight patients (40%) were removed due to drug intolerance (P Ͻ 0.003). The rate of intolerance to TMP/SMX led to the early discontinuation of this randomized trial. Intolerance of TMP/SMX included elevated transaminase levels

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“…14,[16][17][18] Hematologic toxicity was uncommon. 17 Atovaquone tablets, used in earlier studies, have been discontinued due to poor bioavailability.…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

A prospective randomized trial comparing the toxicity and safety of atovaquone with trimethoprim/sulfamethoxazole as Pneumocystis carinii pneumonia prophylaxis following autologous peripheral blood stem cell transplantation

Colby

McAfee

Sackstein

et al. 1999

Bone Marrow Transplant

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“…The stomach, small bowel, and colon are frequently the sites of involvement, even in the absence of detectable disease (22). In addition, hypochlorhydria has been well documented in patients with AIDS (23 (20). In addition, incomplete healthy volunteers (12,15,16,19,26 …”

Section: Methodsmentioning

confidence: 99%

Pharmacokinetics and bioavailability of fluconazole in patients with AIDS

DeMuria

Forrest

Rich

et al. 1993

Antimicrob Agents Chemother

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Fluconazole pharmacokinetics were evaluated for 10 volunteers with AIDS who had no clinical evidence of gastroenteritis. Single 100-mg intravenous (i.v.) and oral (p.o.) doses were administered in a randomized, crossover design. i.v. doses were delivered by a constant-rate infusion over 30 min. Serum fluconazole concentrations were measured by gas-liquid chromatography. The i.v. and p.o. studies were modelled simultaneously by iterative two-stage analysis, which provided individual parameter estimates and a population pharmacokinetic model. Median areas under the concentration-time curves for i.v. and p.o. studies did not differ (90.6 and 99.3 ,ug/ml. h, respectively). Consistent with this finding, the median fractional bioavailability was 1.1 (range, 0.45 to 1.3), comparable to those in healthy subjects. Serum pharmacokinetics in these AIDS patients were generally similar to published data for healthy volunteers. However, foliowing p.o. dosing, we observed a slightly delayed and highly variable time to maximum concentration in serum (median, 2 h; range, 15 min to 8 h). Data were well described by a linear, two-compartment pharmacokinetic model with first-order absorption and elimination. Repeated-measures analysis ofvariance found no significant differences among any of the pharmacokinetic parameters between i.v. and p.o. studies. On the basis of our findings, we suggest no change in dosage of p.o. fluconazole in patients with AIDS who show no clinical signs of enteropathy.Oral (p.o.) fluconazole is frequently administered to persons with AIDS for the treatment of commonly occurring fungal infections, including oropharyngeal and esophageal candidiasis (31) and cryptococcal meningitis (32). Frequently, AIDS patients have hypochlorhydria (23) and other physiologic and anatomic disturbances of the alimentary tract (17,22,25), although gastroenteral symptoms may be absent. Potentially, these factors could interfere with the overall absorption of p.o. administered agents, alter drug transit time, and influence efficacy (11,29).To our knowledge, the absorption of p.o. fluconazole in patients with AIDS has not been investigated. The recommended dosage of p.o. fluconazole for the treatment of fungal infections in patients with AIDS is based upon pharmacokinetic data derived from healthy volunteers (4,14,21). The objective of this study was to determine the p.o. bioavailability and pharmacokinetics of fluconazole in patients with AIDS.(Results of this investigation were presented at the VIIIth International Conference on AIDS/IIIrd STD World Congress, Amsterdam, The Netherlands, July 1992.) MATERIALS AND METHODSPatients and selection criteria. The study population consisted of ambulatory patients who were served by the Brigham and Women's Hospital and the Harvard Community Health Plan (Boston, Mass.). The study protocol was approved by the institutional review boards for human investigation of both institutions. Written informed consent was obtained from each subject.Volunteers who had AIDS (5) were eligible for the stu...

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“…Maximum plasma concentrations exceeded 30000 ng/mL in HIV-infected men dosed with 750 mg ATQ twice daily (16). Further, plasma ATQ concentrations of 10000 -15000 and 15000 -20 000 ng/mL have been associated with 79% and 95% treatment success in patients infected with HIV and presenting with Pneumocystis pneumonia (17). ATQ drug concentrations may be lower if used prophylactically for prevention (10).…”

Section: Discussionmentioning

confidence: 99%

An Ultraperformance LC-MS/MS Method for the Quantification of the Antimalarial Atovaquone in Plasma

Chambliss

Parsons

Marzinke

2017

The Journal of Applied Laboratory Medicine

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Background: A primary modality in the treatment and prevention of malaria is the administration of antimalarial agents. Atovaquone (ATQ) has been used in single-drug and multidrug antimalarial applications; however, studies have demonstrated high interindividual drug variability. With the scarcity of analytical methodologies available in the literature, we have developed and optimized a rapid, ultraperformance (UP) LC-MS/MS method for the quantification of ATQ in human plasma. Methods: ATQ was extracted from 25 μL K 2 -EDTA human plasma via protein precipitation with acetonitrile. Sample solutions were separated on a Synergi 2.5-μm Polar-RP 100A (100 × 2 mm) column. ATQ and its internal standard were detected over 1.3 min on an API 4000 mass analyzer using an electrospray ionization source operated in negative ionization and selected reaction monitoring modes. The method was validated in accordance with the Food and Drug Administration (FDA) Guidance for Industry: Bioanalytical Method Validation recommendations. Results: Owing to pharmacokinetic parameters associated with ATQ, 2 calibration curves were generated to quantify the drug across a dynamic concentration range. Two standard curves were established ranging from 250 to 5000 ng/mL and 5000 to 50000 ng/mL, respectively. QC levels for both lower and higher concentration ranges prepared at low (750 ng/mL, 12000 ng/mL), mid (2000 ng/mL, 22500 ng/mL), and high (4250 ng/mL, 42500 ng/mL) concentrations yielded interassay precision ≤9.1% and accuracy ≤±9.4%. Dilutional, stability, and matrix effects studies were also performed, and results were within acceptability limits. Conclusions: This work describes the development and analytical evaluation of a UPLC-MS/MS method for ATQ quantification in plasma. The described method is sufficiently sensitive for ATQ quantification in plasma to support preclinical and clinical trials.

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Comparison of Atovaquone (566C80) with Trimethoprim-Sulfamethoxazole to Treat Pneumocystis carinii Pneumonia in Patients with AIDS

Abstract: For the treatment of P. carinii pneumonia, atovaquone is less effective than trimethoprim-sulfamethoxazole, but it has fewer treatment-limiting adverse effects.

Cited by 281 publications

References 11 publications

A prospective randomized trial comparing the toxicity and safety of atovaquone with trimethoprim/sulfamethoxazole as Pneumocystis carinii pneumonia prophylaxis following autologous peripheral blood stem cell transplantation

A prospective randomized trial comparing the toxicity and safety of atovaquone with trimethoprim/sulfamethoxazole as Pneumocystis carinii pneumonia prophylaxis following autologous peripheral blood stem cell transplantation

Pharmacokinetics and bioavailability of fluconazole in patients with AIDS

An Ultraperformance LC-MS/MS Method for the Quantification of the Antimalarial Atovaquone in Plasma

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