Atovaquone dosing

The manufacturer of ritonavir predicts that it will decrease the plasma levels of atovaquone, - by inducing atovaquone glucuronidation. They say that the clinical significance of this prediction is unknown, but that an increase in the atovaquone dose might be needed. Careful monitoring of serum levels and/or therapeutic effects is recommended when atovaquone is given with ritonavir as a pharmacokinetic enhancer or as an antiretroviral. This predicted interaction would therefore apply to lopinavir/ritonavir and any other boosted protease inhibitors. However, there does not appear to be any actual data to prove that the interaction occurs or is clinically relevant. 

Atovaquone (Mepron) [Antiprotozoal] Uses Rx prevention PCP Action 4- nucleic acid ATP synth Dose Rx 750 mg PO bid for 21 d Prevention 1500 mg PO once/d (w/ meals) Caution [C, ] Disp Susp SE FevCT, HA, anxiety, insomnia, rash, N/V Interactions X Effects W/ metoclopramide, rifabutin, rifampin, tetracycline EMS None OD Sxs unknown but may cause a rash symptomatic and supportive... 

Atovaquone is a hydroxy-1,4-naphthoquinone, an analog of ubiquinone, with antipneumocystic activity. Since 2000 atovaquone is available as a fixed dose preparation (Malarone) with proguanil for the oral treatment of falciperum malaria. Its activity probably is based on a selective inhibiton of mitochondrial electron transport with consequent inhibition of pyrimidin synthesis. Malarone should not be used to treat severe malaria, when an injectable drug is needed. 

Atovaquone is an alternative therapy for P jiroveci infection, although its efficacy is lower than that of trimethoprim-sulfamethoxazole. Standard dosing is 750 mg taken with food twice daily for 21 days. Adverse effects include fever, rash, nausea, vomiting, diarrhea, headache, and insomnia. Serious adverse effects appear to be minimal, although experience with the drug remains limited. Atovaquone has also been effective in small numbers of immunocompromised patients with toxoplasmosis unresponsive to other agents, although its role in this disease is not yet defined. 

Pneumocystosis, caused by Pneumoq/stis carinii (now classified as a fungus), is an important cause of potentially fatal pneumonia in the immimo-suppressed. It is treated with co-trimoxazole in high dose (120 mg/kg daily in 2-4 divided doses for 14 days by mouth or i.v. infusion). Intolerant or resistant cases may benefit from pentamidine or, if mild to moderate, from atovaquone, or trimetrexate (given with calcium folinate). Co-trimoxazole by mouth or intermittent inhaled pentamidine are used for prophylaxis in patients with AIDS. 

Atovaquone is a hydroxynaphthaquinone that is effective in the prevention and treatment of murine Pneumocystis jiroveci pneumonitis. It also has effects against Toxoplasma gondii and Plasmodium falciparum. Food increases its absorption. The maximum serum concentration is dose-dependent, but absorption is reduced at doses above 750 mg. The maximum concentration occurs after 4-6 hours, with a second peak 24-96 hours later, suggesting enterohepatic cycling. The half-life is 77 hours. 

In a 3-week study with test doses of 100-3000 mg/day, atovaquone was well tolerated. Three patients reported increased appetite two of these had transient sinus arrhythmia. One of the 24 patients had a transient... 

In a prospective efficacy trial of atovaquone suspension (750 mg od or 250 mg tds for 1 year) in P. jiroveci prophylaxis in 28 liver transplant recipients intolerant of co-trimoxazole, the adverse events reported included diarrhea (n — 7) and bloating or abdominal pain (n — 3) (16). No patient had developed P. jiroveci pneumonia by 37 months. This is a smaller dose than approved for Pneumocystis prophylaxis in HIV infection (1500 mg/day). Further studies in recipients of solid organ transplants are needed to confirm the efficacy of this prophylactic dose. 

Atovaquone suspension (1500 mg orally bd) plus either pyrimethamine (75 mg/day after a 200 mg loading dose) or sulfadiazine (1500 mg qds), as treatment for acute Toxoplasma encephalitis (for 6 weeks) and as maintenance therapy (for 42 weeks), has been studied in a randomized phase II trial in HIV-positive patients (17). There were good responses in 21 of 28 patients who received pyrimethamine and nine of 11 who received sulfadiazine. Of 20 patients in the maintenance phase, only one relapsed. Of 40 eligible patients, 11 discontinued treatment as a result of adverse events, nine because of nausea and vomiting or intolerance of the taste of the atovaquone suspension. 

Proguanil is one of the antimalarial drugs most widely used for prophylactic purposes, usually in combination with chloroquine or atovaquone in malaria prophylaxis, and with atovaquone in malaria treatment (SEDA-21, 297). A biguanide, it is rapidly absorbed in standard doses and mainly excreted by the kidneys. Its antimalarial effect is due to its metabolite cycloguanU. However, its metabolism varies individually, and this is reflected in a variable degree of efficacy (SEDA-17, 328). 

The incidence of Pneumocystis carinii pneumonia (PCP) within the first year after transplantation is reported to be 3% to 5%. " Low-dose trimethoprim-sulfamethoxazole (TMP-SMX 400 mg/ 80 mg three times weekly) is effective in the prevention of PCP infections. Alternative agents include aerosolized pentamidine (300 mg every month), dapsone, and atovaquone. The duration of PCP prophylaxis is unclear. The risk of infection caused by P. carinii is likely to decrease as immunosuppression is reduced therefore, prophylaxis in patients requiring treatment for acute rejection may be appropriate. 

In P. falciparum (chloroquine-resistant) infections, a dose of 750 mg mefloquine followed by 500 mg 12 hours later is recommended. The pediatric dose of mefloquine is 15 mg/kg (<45 kg) followed by 10 mg/kg 8 to 12 hours later.Intravenous quinidine gluconate followed by oral quinine should be administered for severe illness, as already indicated.A second drug needs to be administered in chloroquine-resistant P. falciparum, and this second drug should follow the oral quinidine regimen either a single dose of three tablets of pyrimethamine-sulfadoxine (Fansidar) on the last day of intravenous quinidine or clindamycin 900 mg three times daily for 3 to 5 days. An alternative oral treatment for chloroquine-resistant P falciparum infection in adults, especially in those with a history of seizures or psychiatric disorders, is the combination of atovaquone 250 mg and proguanil 100 mg (Malarone) (4 tablets daily... 

In lactating mothers, atovaquone-proguanil is not recommended. Also, the infant must be shown to have a normal G6PD level before using primaquine. For prophylaxis in long-term travelers, chloroquine is safe at the doses used, but may necessitate yearly retinal examinations. Mefloquine and doxycycline are well tolerated. Atovaquone-proguanil has been studied for up to 20 weeks but probably is acceptable for years based on experience with the individual components. 

Zidovudine (AZT) is an HIV reverse transcriptase inhibitor and chain terminator that is extensively glucuronidated (70% of the dose) primarily by UGT2B7. Metabolism of AZT is induced by rifampin (PXR), ritonavir, tipranavir, and efavirenz. Zidovudine clearance is inhibited by methadone (McCance-Katz, 1998) (opiates like codeine and morphine are UGT2B7 substrates), fluconazole Trapnell, 1998, atovaquone (Lee, 1996), and valproate (Lertora, 1994). Rifampin increased the formation clearance to AZT-glucuronide by twofold (Gallicano, 1999). 

Dixon R, Pozniak AL, Watt HM, Rolan P, Posner J. Single-dose and steady-state pharmacdc-inetics of a novel microfluidized su nsion of atovaquone in human immunodeficiency virus-seropositive patients. Antimerob Agents Chemoffter ( 996) 40, 556-60. 

In a pharmacokinetic study in HIV-positive subjects designed to determine the dose of atovaquone suspension that would achieve specific steady-state plasma levels, administration with high-fat food increased the bioavailability of atovaquone by 1.4-fold when compared with the fasted state. In another similar study, administration of atovaquone suspension with food (23 g of fat) increased average steady-state levels by 1.3-fold to 1.7-fold with different dosage regimens (using 500 mg to 1.5 g of atovaquone. ... 

In a single-dose study in healthy subjects, a high-fat breakfast (21 g of fat) increased the AUC of atovaquone by 2.4-fold, and an enteral nutrition supplement (Sustacal Plus, containing 28 g of fat) increased the AUC by 2.7-fold compared with the fasted state. ... 

An isolated report describes a 22-month-old girl treated with phenytoin, sodium valproate and topiramate for epilepsy and then with quinine sulfate (initially intravenously, then orally) followed by a single dose of sul-fadoxine/pyrimethamine for malaria. Her malaria film became negative after 4 days of the 7-day quinine course. About 1 month later she was found to have recrudescent falciparum malaria, which was treated with quinine sulfate and then atovaquone/proguanil. Although it is possible that quinine resistance may have occurred, the authors also considered that enzyme induction by phenytoin may have led to suboptimal quinine levels. Although quinine does not appear to affect phenytoin levels, the isolated case report suggests that levels of quinine may be reduced in the presence of phenytoin and it would seem prudent to monitor carefully concurrent use. 

In 12 healthy subjects, atovaquone (1 g, given both twelve hours before and with a single 600-mg dose of phen i oin) did not affect the pharmacokinetics of phen i oin. It was concluded that a clinically important pharmacokinetic interaction is uniikeiy. ... 

Moderate increases in the AUC of zidovudine, not usually requiring dose adjustments, have been seen with atovaquone. However, it may be prudent to regularly monitor for adverse effects. Atovaquone decreased the AUC of didanosine. Neither didanosine nor zidovudine affected atovaquone pharmacokinetics. 

The manufacturer of atovaquone notes that it decreased the AUC of didanosine by 24% in a multiple dose interaction study. There was no change in the pharmacokinetics of atovaquone. ... 

The manufacturer of atovaquone notes that the decrease in didanosine levels is unlikely to be clinically relevant. They also say that the increased plasma levels of zidovudine likely with a 3-week course of atovaquone for acute Pneumocystis pneumonia are unlikely to increase the adverse effects of zidovudine, and routine dose adjustments are not required. Nevertheless, the manufacturers of atovaquone and zidovudine do recommend reg-... 

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