Foscarnet Foscarnet

DRUG EVALUATION Drugs 41 (I): 104-129, 1991 0012-6667/ 91 /0001-0 I 04/$13.00/0 © Adis International Limited. All rights reserved. DRE1129 Foscarnet A Review of its Antiviral Activity, Pharmacokinetic Properties and Therapeutic Use in Immunocompromised Patients with Cytomegalovirus Retinitis Paul Chrisp and Stephen P. Clissold Adis Drug Information Services, [Auckland, New Zealand Various sections of the manuS¢ript reviewed by:M.M. Fanning, Division ofInfectious Diseases, Toronto General Hospital, Toronto, Ontario, <:;anada; B.G. Gauard, Westminster Hospital, London, England; M.A. Jacobson, Di vision of Infectious Diseases~ i Sa,~ Francisco General Hospital, San Francisco, California, USA; C. Katlama, De partment of Parasitology andI:llfectious Diseases, Groupe Hospitalier Pitie-Salpetriere,Paris, France; I.H. Leopold, Department ofOphthalmolog¥, University of California, Irvine, California, USA; J. Mills, Division ofInfectious Diseases, San Francisco Geiu::ral Hospital, San Francisco, California, USA; B. Oberg, Medivir AB, Huddinge, Sweden; A.I. Pinching, Dep~ftment of ImmunQlogy, St Mary's Hospital Medical School, London, England; O. Ringden, Department of plinical Immunolog~, Karolinska Institute, Huddinge Hospital, Huddinge, Sweden. Contents 105 Summary 107 I. Antiviral Activity 108 l.l In Vit ~~ Activity /08 1.1.1 Ef/feQts on Viral Enzymes /08 1.1.2 Effe¢ts on Viral Replication 110 1.2 In Viv~ Aictivity , 110 1.3 Activi~k df Foscarnet Combined with Other Antiviral Drugs III 1.4 Viral : Re~jstance to Foscamet III 1.5 Mech~~i ~ln of Action , ''''I' ' YI · . , , III 2.. Effect .on i ~q:st Enzymes alld Cells lI2 3. PharmacoRiIibticProperties II ' I J/2 3.1 Plasma <I:pncentrations 113 3.2 DistriBI!l~i~:m 114 3.3 Elljnin~t i~? " . 1/5 3.A Rel"att.o.:;?.s!IJ... IP ~et~e,~n p.la. ~',lla Concentratlo? and V~~~tatIC Effects 1/5 4. Therape~t l, A I ~ se In PatIents'Wlth Cytomegalovirus RetInitis 1/6 4.1 Case ~eports 116 4.2 No~c9~~arativ9 Studies 120 4.3 FoscaOl.I!lei!Compared with!GancicIovir . : l illi I·. ' 121 5. Advers,e 'Effects 121 5. i Reha:!; II II'i '! 122 5.2 H~e ~ aio ~ogical 123 5.3 Metab~ii () 1'" I I 124 5A Misc¢!lallf!0us 125 6. Drug IntHa,ctions 125 JII· •• . 7. Dosage a,,~ !t dmInlstratlOn 126 8. Place of ~~s~rnet in the Management of Cytomegalovirus Retinitis Foscarnet: A Review 105 Summary Synopsis The pyrophosphate analogue. foscarnet. selectively inhibits the DNA polymerase ofhuman herpes viruses. including cytomegalovirus. and the reverse transcriptase ofHIV. Viral replication is there fore prevented. but resumes when the drug is cleared from infected cells. In vitro, the combination offoscarnet and zidovudine (azidothymidine) has an additive effect against cytomegalovirus and acts synergistically against HIV. An improvement in cytomegalovirus retinitis is obtained in over 85% of affected AIDS patients during foscarnet induction therapy. but relapse usually occurs within a month of ceasing treatment. There is a similar duration of remission during maintenance therapy given for 5 days each week. but this can be extended 4- to 5-/01d with daily administration of higher doses. In allograft recip ients. progression' of retinitis can be halted by foscarnet until immune function recovers and erad icates the virus. The incidence of acute renal failure. which is common during foscarnet therapy. may be reduced by dosage adjustment and adequate prehydration. Anaemia. phlebitis. nausea and vomiting. and disturbances in serum calcium and phosphate levels. perhaps resulting from uptake offoscarnet into bone or chelation with ionised calcium. have also been associated with admin istration of the drug. Cytomegalovirus retinitis is difficult to treat. with few therapeutic options available. Although treatment with foscarnet produces some severe adverse effects. with care these can be minimised. and the drug produces clinical improvement in a large proportion of patients; this is a highly encouraging finding at this stage in its development. Preliminary comparative data indicate that foscarnet and ganciclovir are similarly effective, but foscarnet may have some theoretical advan tages in AIDS patients since it can be used in combination with zidovudine without potentiating myelosuppression. Antiviral Activity Foscarnet is a pyrophosphate analogue which prevents replication of herpesviruses, including cytomegalovirus, by inhibiting viral DNA polymerases. 50% inhibition of cytomegalovirus DNA polymerase is achieved by foscarnet 0.3 /llnol/L; other herpesvirus enzymes are similarly sensi tive. Foscarnet also inhibits HIV reverse transcriptase, causing 50% reduction in activity at con centrations of 0.1 to 0.5 /lmol/L. In contrast, inhibition of mammalian DNA polymerase by foscarnet is negligible, with 50% inhibition achieved at a concentration of 40 or 50 /lmol/L. Exposure for at least 18 hours to foscarnet 1000 /lmol/L was required to inhibit DNA synthesis and division of human cell lines by 50%. Human cytomegalovirus plaque formation was inhibited by 50% by foscarnet concentrations between 25 and 34 /lmol/L; clinical isolates were about 3. to 8 times less sensitive. Late antigen expression, a marker of cell death, was prevented by foscarnet 500 /lmol/L only if human fibro blasts were exposed to the drug within 24 hours of cytomegalovirus infection. The virustatic activity of foscarnet is reversible, with antigens to cytomegalovirus expressed 3 to 9 days after foscarnet was removed from cell culture. In vivo, intraperitoneal administration of foscarnet re duced the mortality rate of cytomegalovirus-infected mice by 40%, but was ineffective in guinea pigs. Foscarnet 10 to 25 /lmol/L inhibited in vitro HIV replication by 50%, and 132 /lmol/L caused 98% inhibition of the virus. Inhibition of cytomegalovirus replication in human cell lines is add itive when foscarnet is combined with zidovudine and synergistic with trifluridine (trifluoro thymidine). Synergistic inhibition of IIIV replication occurred with the combination offoscarnet and zidovudine, particularly at higher ratios of foscarnet.- Although resistance of cytomegalpvirus to foscarnet has not been reported either in vitro or clinically, resistant mutants of herpes simplex are readily produced. The lack of susceptibility to foscarnet is conferred by changes in the viral DNA polymerase; at least 3 different drug-resistant variants have been identified. In summary, foscarnet reversibly inhibits cytomegalovirus and HIV replication by blocking DNA polymerase and reverse transcriptase, respectively, at concentrations relatively harmless to host cellular enzymes and division. ' 106 Drugs 41 (J) 1991 Pharmacokinetic Properties Mean steady-state plasma concentrations offoscarnet, achieved after 6 to 21 days' continuous intravenous infusion of foscarnet 0.09 to 0.19 mg/kg/min, were between 228 and 261 ,umol/L in AIDS patients, although there was substantial variation between individuals. With 2-hour infu sions of foscarnet 60 mg/kg given every 8 hours, mean peak and trough plasma concentrations of 495 and 126 ,umol/L were reached after 14 days. The mean apparent volume of distribution of foscarnet in 13 patients with HIV infection was 5.1 L/kg, indicating extensive distribution out of the plasma. No metabolites offoscarnet have been detected. In HIV-infected patients, 83% of a cumulative intravenous dose of foscarnet was recovered unchanged in the urine during the first 36 hours of stopping the infusion, with 88% recovered within a week. The remainder was accounted for by deposition into bone, assuming that excretion of foscarnet is exclusively through the kidneys. Glomerular filtration and tubular secretion contribute almost equally to renal clearance which accounts for 82 to 86% of total plasma clearance of foscarnet. Uptake into bone matrix appears to be responsible for the balance. Sequestration into bone may be responsible for the long terminal phase half-life of foscarnet which was up to a mean of 88 hours. Of more practical value in terms of a dosage schedule are the first and second phase elimination half-lives of foscarnet which were 0.5 to 1.4 hours and 3.3 to 6.8 .hours, respectively. Based on in vitro activity of foscarnet against cytomegalovirus, most investigators have aimed at keeping drug plasma concentrations between 333 and 500 ,umol/L to ensure that virustatic levels are maintained. ' Therapeutic Use In common with other agents used in this condition, clinical experience with foscarnet in the management of patients with cytomegalovirus retinitis is largely limited to noncomparative stud ies involving AIDS patients, and to isolated case reports. Both continuous and intermittent intravenous infusions have been investigated as induction therapy, with the latter approach now preferred because of apparently greater efficacy, conven ience and reduced toxicity. Induction therapy commencing with an intravenous bolus injection of foscarnet 20 or 30 mg/kg followed by a continuous infusion of 230 mg/kg/day for 2 to 4 weeks elicits a complete response in 50 to 75% of patients, and a partial response in about 10 to 50%. The overall response rate is over 85%. Continuous infusions have now largely been superseded by the alternative induction regimen of infusion of foscarnet60 mg/kg every 8 hours or 100 mg/kg every 12 hours for 2 to 4 weeks, resulting in an overall 'response rate of over 88%, with partial responses predominating. Because relapse occurs in approximately 66% of surviving patients within a, month of stopping induction therapy, subsequent maintenance

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