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Buying Time: The Use of Extracorporeal Membrane Oxygenation as a Bridge to Lung Transplantation in Pediatric Patients
Abstracts 811 Characterization of the Lung Microbiome in Pediatric Lung Transplant Recipients R.A. Luna1 M. Sagar,2 S.A. Crabtree,2 E.B. Hollister,1 J.K. Runge,1 Y. Shang,1 J.S. Heinle,3 E.D. McKenzie,3 G.B. Mallory,2 M.G. Schecter.2 1Microbiome Center, Department of Pathology, Immunology, Texas Children’s Hospital, Houston, TX; 2Pulmonology, Texas Children’s Hospital, Houston, TX; 3Cardiovascular Surgery, Texas Children’s Hospital, Houston, TX. Purpose: Lung transplant is a therapeutic option for end stage lung disease in children. Cystic Fibrosis (CF) is the leading indication for lung transplant in children. The lung microbiome has been characterized in other lung diseases but not in lung transplant recipients (LTRs). Infection is associated with increased morbidity and mortality in LTRs. The purpose of our study is to characterize the lung microbiome in children who have undergone lung transplantation. In addition, we hypothesize that there will be differences in the lung microbiome between non-transplant and transplant patients. Methods and Materials: Ninety-four bronchoalveolar lavage specimens from 21 patients were collected during surveillance bronchoscopies throughout the first year post-transplant. Bacterial DNA was extracted, and the V3V5 variable regions of the 16SrRNA gene were amplified using universal barcoded primers. Subsequent 454 sequencing produced an average of 6,000 reads per sample with an average length of 500 bases. Resulting sequences were analyzed by the Genboree Microbiome Workbench. Results: Most abundant phylum in LTRs was Proteobacteria followed by Firmicutes. Acinetobacter was the most prevalent genus in LTRs. This in contrast to previous microbiome studies in non-transplanted CF patients where Firmicutes was the predominant phylum. Bacterial diversity increased until 9 months post transplant. However, there was a decrease in bacterial diversity between 9 and 12 months. Longitudinal analysis also showed increased Streptococcus at 3 months post-transplant in LTRs. Results of lung microbiome correlated well with traditional cultures. Conclusions: The predominant phylum is Proteobacteria and Acinetobacter is the most prevalent genus in LTRs which differs from the reported microbiome description in other lung diseases. Bacterial diversity initially increases in LTRs but then decreased by 1 year post transplant. The clinical implication of these findings of the lung microbiome on the morbidity and mortality in LTRs requires further investigation. 812 Early Echocardiographic Predictors of Alveolar Capillary Dysplasia: A Case-Control Study R. Arcinue,1 T. Stavroudis,1 S. Noori,1 S. Bhombal,1,2 J. Szmuszkovicz,2 P. Friedlich.1 1Center for Fetal and Neonatal Medicine, Children’s Hospital Los Angeles, Los Angeles, CA; 2Pediatric Cardiology, Children’s Hospital Los Angeles, Los Angeles, CA. Purpose: To evaluate early echocardiographic measures of pulmonary hypertension and refractory hypoxemia in patients with ACD and matched controls. Methods and Materials: A retrospective case-control study at a quaternary hospital was conducted from 2000 to 2011. ACD patients were compared to patients with meconium aspiration syndrome ⫾ sepsis matched by gestational age and birthweight. All patients were on inhaled nitric oxide and ECMO. Demographics, onset of illness, presence of congenital anomalies, respiratory, and echocardiographic variables were studied. Two independent cardiologists, blinded to the identity of the cases and controls, prospectively reviewed the first admission echocardiograms. Results: Five patients were identified with ACD by histopathology and matched to 5 controls. Demographics, onset of illness, presence of congenital anomalies, and respiratory variables were not statistically significant between the groups. Excellent inter-rater reliability readings of the echocardiograms between the two cardiologists were achieved (Kappa 0.75-1). There was no statistical difference in the tricuspid regurgitation
S291 (TR) velocities between the two groups; all ACD cases and 75% of the controls had TR velocities Z 3.2 m/sec. More ACD cases had moderate to severe tricuspid jet regurgitation (80% vs. none, po0.01); moderate to severe right atrial enlargement (RAE) (100% vs. none, po0.01); moderate to severe right ventricular (RV) dilatation (100% vs. none, po0.01); and moderately to severely depressed RV function (60% vs. none, po0.01). ACD patients were 11 times more likely to have a combination of moderate to severe RAE and moderate to severe tricuspid jet regurgitation compared to controls (OR ¼ 11.6 [2-68]). Conclusions: The combination of moderate to severe RAE and tricuspid jet regurgitation unresponsive to maximal interventions should alert clinicians of the possibility for ACD. We speculate that early echocardiographic measures may identify at risk neonates for fatal ACD in the first postnatal week and lead to early enlistment for lung transplant. 813 Anti-Fungal Prophylaxis in Pediatric Lung Transplantation – An International Multi-Center Survey L. Mead,1 L.A. Danziger-Isakov,2 M.G. Michaels,3 S.B. Goldfarb,4 A.R. Glanville,1 C. Benden.5 1St Vincent’s Hospital, Sydney, Australia; 2 Cincinnati Children’s Hospital, Cincinnati, OH; 3Children’s Hospital of Pittsburgh, Pittsburgh, PA; 4The Children’s Hospital of Philadelphia, Philadelphia, PA; 5University Hospital Zurich, Zurich, Switzerland. Purpose: Fungal infections pose a significant risk to children following lung transplantation. However, there are at present no internationally agreed upon guidelines for anti-fungal prophylaxis, and current clinical practice varies. The aim of this survey was to ascertain the current strategies of anti-fungal prophylaxis of pediatric lung transplant centers. Methods and Materials: In 2012, nominated clinicians at each of the 24 centers within the International Pediatric Lung Transplant Collaborative (IPLTC) were invited to participate in a web-based, selfadministered survey on strategies of anti-fungal prophylaxis adopted at their institution. Responders were asked to complete the survey via a combination of multiple choice and free text answers. Results: 19 (79%) centers responded to the survey. Centers were predominantly located in the US and Europe, 450% of centers perform pediatric and adult lung transplants. The majority of centers (78%) routinely use pre-emptive/targeted prophylaxis, mainly in patients with pre-transplant fungal colonization. Commonly, institutions aim to target Aspergillus and Candida infection, whilst most choose to use monotherapy, mainly voriconazole or inhaled amphotericine B. Centers employ prophylaxis for variable amounts of time (42% r3 months, 42% for Z12 months). The reasons to change to alternative drugs were intolerability, toxicity or positive surveillance culture. 88% of centers utilize therapeutic drug monitoring. Conclusions: This survey has identified a wide range of anti-fungal prophylaxis strategies adopted internationally in the pediatric lung transplant population. There is growing approval for the formation of internationally agreed upon guidelines within the pediatric lung transplant community. 814 Buying Time: The Use of Extracorporeal Membrane Oxygenation as a Bridge to Lung Transplantation in Pediatric Patients G. Casswell1 D. Pilcher,2 R. Martin,1 V. Pelligrino,2 S. Marasco,1 C. Robertson,3 W. Butt,4 G.I. Snell,1 G.P. Westall.1 1Lung Transplant Servive, The Alfred Hospital, Melbourne, Australia; 2Intensive Care Unit, The Alfred, Melbourne, Australia; 3Department of Respiratory Medicine, Royal Children’s Hospital, Melbourne, Australia; 4Intensive Care Unit, Royal Children’s Hospital, Melbourne, Australia. Purpose: To describe our experience to date of 4 children with end stage lung disease who have been bridged with Extracorporeal Membrane Oxygenation (ECMO) to successful lung transplantation (LTx) in our institution. Methods and Materials: Between March 2006 and June 2012, a total of 21 pediatric patients (aged 6 to 17 years of age) successfully underwent LTx within The Alfred’s combined adult and pediatric lung
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transplantation program. This included 4 children who were bridged on ECMO prior to LTx according to the ‘‘ECMO bridge to transplant’’ protocol, and whose clinical notes and outcomes were reviewed. Results: The four pediatric patients who were ECMO bridged to LTx were compared to 17 pediatric patients who were transplanted over the same time period but did not require ECMO prior to LTx. Three month survival was 88.2% in those who were not bridged from ECMO and 100% for patients who were bridged to LTx by ECMO. Two patients underwent cut-down lobar LTx. The median length of stay in ICU post LTx was 14 days in the ECMO group compared to 7 days in the non ECMO group of patients (See table 3). The total length of post-operative hospital stay was also greater in the ECMO group with a median of 32 days compared with 25 days in the patients without ECMO support. Conclusions: Whilst our report describes excellent short and mediumterm outcomes in a small number of children who have been bridged to transplant on ECMO, it is important to re-iterate that the very the decision to offer ECMO should be made on a case-by-case basis and that best transplant outcomes will arise when potential transplant recipients are identified early, are educated with regard to transplantation, and engage in pulmonary rehabilitation whilst on the waiting list. 815 A Single Center Transition of Care Model from Pediatric Heart to Adult Services S. Adams, M. Wigger. Heart Transplant, Vanderbilt, Nashville, TN. Purpose: This first transition year has shown to have increased instances of rejection, graft dysfunction, and death. There is little data or guidelines to transition young adults to adult centered transplant programs. There are no current ISHLT guidelines to establish a transition program. We have two years of data gathered from 2010 to the present from our program. Methods and Materials: Benchmarks that have been identified to measure the success of the transition are the following indicators:1.Number of Rejection events. 2. Stable allomap scores and IS levels. 3.Consistent clinical compliance, continued stable mental health -with minimal life style changes/impairment 4. Work/School. Family goals with engagement in departmental return to work program, participation in pregnancy counseling.5. ED visits/hospitalization/ discharges. Results: Year to date 12 patients have transitioned. The mean time post transplant has been 12 years. Median age has been 24 years. We have 2 patient deaths; 1 from humoral rejection due to medical noncompliance and 1 patient died from suicide. 5 patients have successfully entered the work force or are attending college.10 others have had good compliance and stable IS/ Allomap levels. There have been no pregnancies reported in our transition program. All 12 patients have been hospitalized for causes including: infection, rejection, rhythm issues, and other end organ failure. Conclusions: Initial outcomes shows complexity of establishing a transition program. It is imperative to build an effective transitional care model/program with evidenced based practice without loss of life or graft function. Lessons learned include establishing better education and pre- planning from a peds oriented program to an adult oriented program, establishing a care coordinator to help this special transition population, administrative and financial support, timing of transition criteria (coincide age related mile stones), confidence in the adult team, and establishing peds to adult oriented quality of life benchmarks.
Purpose: Sirolimus may reduce the development of coronary vasculopathy and calcineurin inhibitor (CNI)-induced nephropathy in adult heart transplant patients. We report our experience with sirolimus as a primary immunosuppressive agent in pediatric heart transplant patients. Methods and Materials: We retrospectively reviewed records for all pediatric heart transplant patients for whom we attempted conversion to a CNI-free sirolimus-based regimen. Patients were treated routinely with an anti-metabolite medication in addition to sirolimus, with or without steroids. We examined records for demographics, episodes of rejection, and serum measures of renal function. Results: We identified 18 patients (mean age at transplant 7.8 years, range 0.1–21 yrs, 45% female) for whom we attempted conversion to a sirolimus-based regimen an average of 39⫾46 months post transplant. Of these 18, 4 patients had to discontinue sirolimus due to side effects (pneumonitis, aphthous ulcers, proteinuria, and dactylitis). The remaining 14 patients (mean age at transplant 7.6 years, range 0.1–21 yrs, 43% female) were successfully converted over a period of 88⫾52 days to the CNI-free immunosuppressive protocol. Follow-up was available for an average of 2.7⫾2.6 years post-conversion. For these 14 patients, there was no significant difference between the rate of rejection while taking CNIs prior to conversion (0.21 rejection episodes per patient-year) compared to post-conversion (0 rejection episodes per patient-year). Serum creatinine was decreased from 1.0⫾0.6 mg/dL pre-conversion to 0.8⫾0.4 post-conversion, and 0.8⫾0.6 at latest follow-up, however this did not reach statistical significance. Conclusions: In this small cohort, a CNI-free sirolimus-based immunosuppressive regimen was not associated with an increased rejection rate or change in markers of renal function. The use of sirolimus as a primary agent in pediatric heart transplant patients warrants further evaluation. 817 SLCO1B1 Genotype Influences the Drug-Drug Interaction between Cyclosporine and Pravastatin C.L. Aquilante,1 R.L. Page II2 A. Brieke,3 C.W. Hopley,1 U. Christians,4 K.L. Hoffman,4 B. Schniedewind.4 1Department of Pharmaceutical Sciences, University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, CO; 2Department of Clinical Pharmacy, University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, CO; 3Division of Cardiology, University of Colorado School of Medicine, Aurora, CO; 4Department of Anesthesiology, University of Colorado School of Medicine, Aurora, CO. Purpose: Cyclosporine (CYA) increases pravastatin (PRAV) plasma exposure by inhibiting the OATP1B1 (SLCO1B1) transporter. The aim of this study was to determine if the SLCO1B1 c.521 T4C polymorphism influences pharmacokinetic (PK) variability in the magnitude of the drug-drug interaction between CYA and PRAV. Methods and Materials: Healthy adults were enrolled based on SLCO1B1 c.521 genotype (T/T n¼23; T/C n¼8; C/C n¼1). In phase 1, subjects received PRAV 20 mg x 1 dose. In phase 2, subjects received CYA 1.25 mg/kg x 2 doses, with PRAV 20 mg given 1 hr after the 2nd CYA dose. A 12-hr PK study followed each PRAV dose, with a 7-day washout between phases. PRAV (parent) and SQ31906 (metabolite) plasma concentrations were measured with LC-MS/MS. PK parameters were generated for PRAVþSQ31906 (PRAVtotal). Results: The study included 19 women and 13 men, with a mean age of 29 ⫾ 5 yrs. CYA increased PRAVtotal AUC0-12 by 4.7-fold (range 1.6 to 10.8-fold; Po0.001). Following CYA administration, subjects with the SLCO1B1 c.521 T/T genotype had a larger increase in
816 Calcineurin Inhibitor-Free Immunosuppression in Pediatric Heart Transplantation Recipients: Sirolimus as a Primary Immunosuppressive Agent R.W. Loar,1 D.A. Mauriello,2 P.W. O’Leary,2 D.J. Driscoll,2 S.S. Kushwaha,3 J.N. Johnson.2 1Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN; 2Pediatric Cardiology, Mayo Clinic, Rochester, MN; 3Cardiovascular Diseases, Mayo Clinic, Rochester, MN.
PRAVtotal Parameter Phase
c.521 T/T
AUC0-12 (ngh/ml)
91 ⫾ 51 106 ⫾ 40 425 ⫾ 185 325 ⫾ 114 5.3 (2.5–10.8) 3.2 (1.6–4.8) 44 ⫾ 28 52 ⫾ 23 232 ⫾ 120 182 ⫾ 90 6.9 (2.4–17.0) 3.7 (1.5–6.8) genotype groups
PRAV PRAVþCYA Relative Change Cmax (ng/ml) PRAV PRAVþCYA Relative Change Mean⫾SD (range); P values, between
c.521 T/C or C/C P value 0.26 0.13 0.008 0.10 0.23 0.003
S291 (TR) velocities between the two groups; all ACD cases and 75% of the controls had TR velocities Z 3.2 m/sec. More ACD cases had moderate to severe tricuspid jet regurgitation (80% vs. none, po0.01); moderate to severe right atrial enlargement (RAE) (100% vs. none, po0.01); moderate to severe right ventricular (RV) dilatation (100% vs. none, po0.01); and moderately to severely depressed RV function (60% vs. none, po0.01). ACD patients were 11 times more likely to have a combination of moderate to severe RAE and moderate to severe tricuspid jet regurgitation compared to controls (OR ¼ 11.6 [2-68]). Conclusions: The combination of moderate to severe RAE and tricuspid jet regurgitation unresponsive to maximal interventions should alert clinicians of the possibility for ACD. We speculate that early echocardiographic measures may identify at risk neonates for fatal ACD in the first postnatal week and lead to early enlistment for lung transplant. 813 Anti-Fungal Prophylaxis in Pediatric Lung Transplantation – An International Multi-Center Survey L. Mead,1 L.A. Danziger-Isakov,2 M.G. Michaels,3 S.B. Goldfarb,4 A.R. Glanville,1 C. Benden.5 1St Vincent’s Hospital, Sydney, Australia; 2 Cincinnati Children’s Hospital, Cincinnati, OH; 3Children’s Hospital of Pittsburgh, Pittsburgh, PA; 4The Children’s Hospital of Philadelphia, Philadelphia, PA; 5University Hospital Zurich, Zurich, Switzerland. Purpose: Fungal infections pose a significant risk to children following lung transplantation. However, there are at present no internationally agreed upon guidelines for anti-fungal prophylaxis, and current clinical practice varies. The aim of this survey was to ascertain the current strategies of anti-fungal prophylaxis of pediatric lung transplant centers. Methods and Materials: In 2012, nominated clinicians at each of the 24 centers within the International Pediatric Lung Transplant Collaborative (IPLTC) were invited to participate in a web-based, selfadministered survey on strategies of anti-fungal prophylaxis adopted at their institution. Responders were asked to complete the survey via a combination of multiple choice and free text answers. Results: 19 (79%) centers responded to the survey. Centers were predominantly located in the US and Europe, 450% of centers perform pediatric and adult lung transplants. The majority of centers (78%) routinely use pre-emptive/targeted prophylaxis, mainly in patients with pre-transplant fungal colonization. Commonly, institutions aim to target Aspergillus and Candida infection, whilst most choose to use monotherapy, mainly voriconazole or inhaled amphotericine B. Centers employ prophylaxis for variable amounts of time (42% r3 months, 42% for Z12 months). The reasons to change to alternative drugs were intolerability, toxicity or positive surveillance culture. 88% of centers utilize therapeutic drug monitoring. Conclusions: This survey has identified a wide range of anti-fungal prophylaxis strategies adopted internationally in the pediatric lung transplant population. There is growing approval for the formation of internationally agreed upon guidelines within the pediatric lung transplant community. 814 Buying Time: The Use of Extracorporeal Membrane Oxygenation as a Bridge to Lung Transplantation in Pediatric Patients G. Casswell1 D. Pilcher,2 R. Martin,1 V. Pelligrino,2 S. Marasco,1 C. Robertson,3 W. Butt,4 G.I. Snell,1 G.P. Westall.1 1Lung Transplant Servive, The Alfred Hospital, Melbourne, Australia; 2Intensive Care Unit, The Alfred, Melbourne, Australia; 3Department of Respiratory Medicine, Royal Children’s Hospital, Melbourne, Australia; 4Intensive Care Unit, Royal Children’s Hospital, Melbourne, Australia. Purpose: To describe our experience to date of 4 children with end stage lung disease who have been bridged with Extracorporeal Membrane Oxygenation (ECMO) to successful lung transplantation (LTx) in our institution. Methods and Materials: Between March 2006 and June 2012, a total of 21 pediatric patients (aged 6 to 17 years of age) successfully underwent LTx within The Alfred’s combined adult and pediatric lung
S292
The Journal of Heart and Lung Transplantation, Vol 32, No 4S, April 2013
transplantation program. This included 4 children who were bridged on ECMO prior to LTx according to the ‘‘ECMO bridge to transplant’’ protocol, and whose clinical notes and outcomes were reviewed. Results: The four pediatric patients who were ECMO bridged to LTx were compared to 17 pediatric patients who were transplanted over the same time period but did not require ECMO prior to LTx. Three month survival was 88.2% in those who were not bridged from ECMO and 100% for patients who were bridged to LTx by ECMO. Two patients underwent cut-down lobar LTx. The median length of stay in ICU post LTx was 14 days in the ECMO group compared to 7 days in the non ECMO group of patients (See table 3). The total length of post-operative hospital stay was also greater in the ECMO group with a median of 32 days compared with 25 days in the patients without ECMO support. Conclusions: Whilst our report describes excellent short and mediumterm outcomes in a small number of children who have been bridged to transplant on ECMO, it is important to re-iterate that the very the decision to offer ECMO should be made on a case-by-case basis and that best transplant outcomes will arise when potential transplant recipients are identified early, are educated with regard to transplantation, and engage in pulmonary rehabilitation whilst on the waiting list. 815 A Single Center Transition of Care Model from Pediatric Heart to Adult Services S. Adams, M. Wigger. Heart Transplant, Vanderbilt, Nashville, TN. Purpose: This first transition year has shown to have increased instances of rejection, graft dysfunction, and death. There is little data or guidelines to transition young adults to adult centered transplant programs. There are no current ISHLT guidelines to establish a transition program. We have two years of data gathered from 2010 to the present from our program. Methods and Materials: Benchmarks that have been identified to measure the success of the transition are the following indicators:1.Number of Rejection events. 2. Stable allomap scores and IS levels. 3.Consistent clinical compliance, continued stable mental health -with minimal life style changes/impairment 4. Work/School. Family goals with engagement in departmental return to work program, participation in pregnancy counseling.5. ED visits/hospitalization/ discharges. Results: Year to date 12 patients have transitioned. The mean time post transplant has been 12 years. Median age has been 24 years. We have 2 patient deaths; 1 from humoral rejection due to medical noncompliance and 1 patient died from suicide. 5 patients have successfully entered the work force or are attending college.10 others have had good compliance and stable IS/ Allomap levels. There have been no pregnancies reported in our transition program. All 12 patients have been hospitalized for causes including: infection, rejection, rhythm issues, and other end organ failure. Conclusions: Initial outcomes shows complexity of establishing a transition program. It is imperative to build an effective transitional care model/program with evidenced based practice without loss of life or graft function. Lessons learned include establishing better education and pre- planning from a peds oriented program to an adult oriented program, establishing a care coordinator to help this special transition population, administrative and financial support, timing of transition criteria (coincide age related mile stones), confidence in the adult team, and establishing peds to adult oriented quality of life benchmarks.
Purpose: Sirolimus may reduce the development of coronary vasculopathy and calcineurin inhibitor (CNI)-induced nephropathy in adult heart transplant patients. We report our experience with sirolimus as a primary immunosuppressive agent in pediatric heart transplant patients. Methods and Materials: We retrospectively reviewed records for all pediatric heart transplant patients for whom we attempted conversion to a CNI-free sirolimus-based regimen. Patients were treated routinely with an anti-metabolite medication in addition to sirolimus, with or without steroids. We examined records for demographics, episodes of rejection, and serum measures of renal function. Results: We identified 18 patients (mean age at transplant 7.8 years, range 0.1–21 yrs, 45% female) for whom we attempted conversion to a sirolimus-based regimen an average of 39⫾46 months post transplant. Of these 18, 4 patients had to discontinue sirolimus due to side effects (pneumonitis, aphthous ulcers, proteinuria, and dactylitis). The remaining 14 patients (mean age at transplant 7.6 years, range 0.1–21 yrs, 43% female) were successfully converted over a period of 88⫾52 days to the CNI-free immunosuppressive protocol. Follow-up was available for an average of 2.7⫾2.6 years post-conversion. For these 14 patients, there was no significant difference between the rate of rejection while taking CNIs prior to conversion (0.21 rejection episodes per patient-year) compared to post-conversion (0 rejection episodes per patient-year). Serum creatinine was decreased from 1.0⫾0.6 mg/dL pre-conversion to 0.8⫾0.4 post-conversion, and 0.8⫾0.6 at latest follow-up, however this did not reach statistical significance. Conclusions: In this small cohort, a CNI-free sirolimus-based immunosuppressive regimen was not associated with an increased rejection rate or change in markers of renal function. The use of sirolimus as a primary agent in pediatric heart transplant patients warrants further evaluation. 817 SLCO1B1 Genotype Influences the Drug-Drug Interaction between Cyclosporine and Pravastatin C.L. Aquilante,1 R.L. Page II2 A. Brieke,3 C.W. Hopley,1 U. Christians,4 K.L. Hoffman,4 B. Schniedewind.4 1Department of Pharmaceutical Sciences, University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, CO; 2Department of Clinical Pharmacy, University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, CO; 3Division of Cardiology, University of Colorado School of Medicine, Aurora, CO; 4Department of Anesthesiology, University of Colorado School of Medicine, Aurora, CO. Purpose: Cyclosporine (CYA) increases pravastatin (PRAV) plasma exposure by inhibiting the OATP1B1 (SLCO1B1) transporter. The aim of this study was to determine if the SLCO1B1 c.521 T4C polymorphism influences pharmacokinetic (PK) variability in the magnitude of the drug-drug interaction between CYA and PRAV. Methods and Materials: Healthy adults were enrolled based on SLCO1B1 c.521 genotype (T/T n¼23; T/C n¼8; C/C n¼1). In phase 1, subjects received PRAV 20 mg x 1 dose. In phase 2, subjects received CYA 1.25 mg/kg x 2 doses, with PRAV 20 mg given 1 hr after the 2nd CYA dose. A 12-hr PK study followed each PRAV dose, with a 7-day washout between phases. PRAV (parent) and SQ31906 (metabolite) plasma concentrations were measured with LC-MS/MS. PK parameters were generated for PRAVþSQ31906 (PRAVtotal). Results: The study included 19 women and 13 men, with a mean age of 29 ⫾ 5 yrs. CYA increased PRAVtotal AUC0-12 by 4.7-fold (range 1.6 to 10.8-fold; Po0.001). Following CYA administration, subjects with the SLCO1B1 c.521 T/T genotype had a larger increase in
816 Calcineurin Inhibitor-Free Immunosuppression in Pediatric Heart Transplantation Recipients: Sirolimus as a Primary Immunosuppressive Agent R.W. Loar,1 D.A. Mauriello,2 P.W. O’Leary,2 D.J. Driscoll,2 S.S. Kushwaha,3 J.N. Johnson.2 1Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN; 2Pediatric Cardiology, Mayo Clinic, Rochester, MN; 3Cardiovascular Diseases, Mayo Clinic, Rochester, MN.
PRAVtotal Parameter Phase
c.521 T/T
AUC0-12 (ngh/ml)
91 ⫾ 51 106 ⫾ 40 425 ⫾ 185 325 ⫾ 114 5.3 (2.5–10.8) 3.2 (1.6–4.8) 44 ⫾ 28 52 ⫾ 23 232 ⫾ 120 182 ⫾ 90 6.9 (2.4–17.0) 3.7 (1.5–6.8) genotype groups
PRAV PRAVþCYA Relative Change Cmax (ng/ml) PRAV PRAVþCYA Relative Change Mean⫾SD (range); P values, between
c.521 T/C or C/C P value 0.26 0.13 0.008 0.10 0.23 0.003