title: Coadministration of neoral and the novel rapamycin analog, SDZ RAD, to rat lung allograft recipients: potentiation of immunosuppressive efficacy and improvement of tolerability of staggered versus simultaneous treatment.
abstract: BACKGROUND
  Neoral and rapamycin derivative (RAD) have complementary mechanisms for inhibition of lymphocyte activation and are substrates for the same pathways of drug metabolism. Therefore, we investigated treatment regimens designed to minimize pharmacokinetic interactions and to potentiate immunosuppressive efficacy in a highly stringent rat lung allograft model.
  
  
  METHODS
  Lewis recipients of Brown Norway lungs received the following daily oral doses: (A) RAD at 2.5 mg/kg (n=9); (B) Neoral at 7.5 mg/kg (n=8); (C) RAD at 2.5 mg/kg + Neoral at 7.5 mg/kg simultaneously (n=8); or (D) RAD at 2.5 mg/kg + Neoral at 7.5 mg/kg (n=6) staggered 6 hr apart. Rats were assessed by daily weights, chest radiographs, drug trough levels (high-performance liquid chromatography/mass spectrometry), and blinded scoring of graft histology at death (day 21).
  
  
  RESULTS
  Radiographs were completely opacified in all grafts of control and RAD monotherapy groups on days 7 and 14, respectively. Grafts were mildly opacified (Neoral monotherapy) and completely clear (both RAD + Neoral groups) on day 21. Simultaneous or staggered combined treatment dramatically reduced histologic rejection compared with treatment with either drug alone. Simultaneous treatment caused poor tolerability (poor grooming, lethargy) and significantly higher day-14 RAD and cyclosporine (CsA) trough levels (49+/-5 and 638+/-106 ng/ml; P<0.04) than in the staggered group (28+/-3 and 318+/-25 ng/ml) in which all animals were clinically normal. RAD and CsA day-14 trough levels in the staggered group were the same or lower than trough levels in animals treated with either drug alone (RAD 27+/-3/Neoral 815+/-67 ng/ml).
  
  
  CONCLUSIONS
  (1) Administration of RAD + Neoral suppressed lung rejection more effectively than treatment with either drug alone. (2) Trough levels did not differ between monotherapy and staggered combination therapy for RAD but were lower for CsA. These results suggested that pharmacological, rather than pharmacokinetic, interactions between the parent drugs were responsible for the potentiation of immunosuppression when these drugs were coadministered. 3) Staggered administration of RAD+Neoral avoided the pharmacokinetic interactions that caused the elevated drug blood levels and poor tolerability caused by simultaneous administration. Thus, we could potentiate efficacy and improve tolerability by staggering administration of RAD and Neoral.
authors.affiliation: Transplantation Immunology, Department of Cardiothoracic Surgery, Stanford University, Palo Alto, California 94305, USA.
authors.forename: B
authors.initials: B
authors.lastname: Hausen
authors.forename: K
authors.initials: K
authors.lastname: Boeke
authors.forename: G J
authors.initials: GJ
authors.lastname: Berry
authors.forename: I
authors.initials: I
authors.lastname: Segarra
authors.forename: L Z
authors.initials: LZ
authors.lastname: Benet
authors.forename: U
authors.initials: U
authors.lastname: Christians
authors.forename: R E
authors.initials: RE
authors.lastname: Morris
mesh_terms: D000818:Animals; D001835:Body Weight / Q000187:drug effects; D016572:Cyclosporine / Q000097:blood / Q000627:therapeutic use*; D004338:Drug Combinations; D000068338:Everolimus; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D008168:Lung / Q000000981:diagnostic imaging / Q000187:drug effects / Q000473:pathology; D016040:Lung Transplantation; D008297:Male; D011182:Postoperative Care; D013902:Radiography, Thoracic; D051381:Rats; D011914:Rats, Inbred BN; D011917:Rats, Inbred Lew; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000097:blood / Q000627:therapeutic use; D014184:Transplantation, Homologous
chemical_list: D004338:Drug Combinations; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D000068338:Everolimus; D020123:Sirolimus