The impact of cytochrome P450 3A5 genotype on early tacrolimus metabolism and clinical outcomes in lung transplant recipients

Abstract Background The utility and clinical impact of therapeutic drug monitoring (TDM) of prophylactic azole antifungals in lung transplant recipients is not well described. The objective of this study was to investigate the impact of TDM of azole prophylaxis in lung transplant recipients on the development of positive fungal events. Methods A retrospective analysis was performed on 47 lung transplant recipients between 2013 and 2018 at Northwestern Memorial Hospital. A positive fungal event was defined as fungal species on BAL culture and/or positive BAL Aspergillus galactomannan (GM) with an index value ≥1.0. Study groups were defined based on attainment of therapeutic trough levels after initiation of oral therapy (therapeutic if posaconazole level ≥0.7 μg/mL or voriconazole ≥1–5.5 μg/mL, subtherapeutic if ≥2 consecutive levels of posaconazole <0.7 μg/mL or voriconazole <1 μg/mL after initial dose increase). Results There were no differences in baseline characteristics (Figure 1). There were a total of 11 fungal events with 3 (12.0%) occurring in the therapeutic cohort and 8 (36.4%) in those subtherapeutic (P = 0.08). In the 5 patients with a positive GM, the mean index was 2.02 ± 0.95. 7/30 (23.3%) of patients on posaconazole had a fungal event, with 2/7 (28.6%) requiring treatment at the time of event. For patients on voriconazole, 4/17 (23.5%) had a fungal event, with 1/4 (25.0%) requiring treatment. Mean time to fungal event was 164.5 ± 8.9 days vs. 135.9 ± 13.7 days in the therapeutic and subtherapeutic group, respectively (P = 0.05). All patients on posaconazole suspension who experienced a fungal event were subtherapeutic (3/3, 100%) compared with the majority of patients on posaconazole delayed release (DR) tablets who achieved therapeutic levels (17/22, 77.3%). Mean posaconazole trough level observed in the patients receiving DR tablet was 2.15 ± 0.95 μg/mL. Conclusion There was an association between two consecutive subtherapeutic azole prophylaxis levels and positive fungal events indicating a role for TDM in lung transplant recipients. Time to fungal event post-transplant was shorter in subtherapeutic patients. As anticipated, the use of posaconazole suspension resulted in subtherapeutic levels. This study presents an opportunity for further research of the impact of TDM on clinical outcomes to optimize patient care. Disclosures All authors: No reported disclosures.

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The Impact of Pandemic Influenza A H1N1 2009 on Australian Lung Transplant Recipients

American Journal of Transplantation ◽

10.1111/j.1600-6143.2010.03422.x ◽

2011 ◽

Vol 11 (3) ◽

pp. 568-574 ◽

Cited By ~ 35

Author(s):

B. J. H. Ng ◽

A. R. Glanville ◽

G. Snell ◽

M. Musk ◽

M. Holmes ◽

...

Keyword(s):

Pandemic Influenza ◽

Influenza A ◽

Lung Transplant ◽

Transplant Recipients ◽

Influenza A H1n1 ◽

Lung Transplant Recipients ◽

The Impact

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The impact of genetic polymorphisms, diltiazem, and demographic variables on everolimus trough concentrations in lung transplant recipients

Clinical Transplantation ◽

10.1111/ctr.12350 ◽

2014 ◽

Vol 28 (5) ◽

pp. 590-597 ◽

Cited By ~ 14

Author(s):

Kelly E. Schoeppler ◽

Christina L. Aquilante ◽

Tyree H. Kiser ◽

Douglas N. Fish ◽

Martin R. Zamora

Keyword(s):

Genetic Polymorphisms ◽

Lung Transplant ◽

Demographic Variables ◽

Transplant Recipients ◽

Trough Concentrations ◽

Lung Transplant Recipients ◽

The Impact

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The Impact of Intravenous Immunoglobulin in Sensitized Lung Transplant Recipients with a cPRA <25%

The Journal of Heart and Lung Transplantation ◽

10.1016/j.healun.2017.01.1171 ◽

2017 ◽

Vol 36 (4) ◽

pp. S410

Author(s):

A.L. Hulbert ◽

C. Benedetti ◽

K. Beermann ◽

A. Gray ◽

M. Hartwig ◽

...

Keyword(s):

Intravenous Immunoglobulin ◽

Lung Transplant ◽

Transplant Recipients ◽

Lung Transplant Recipients ◽

The Impact

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Human Cytomegalovirus (HCMV)-Specific Antibody Response and Development of Antibody-Dependent Cellular Cytotoxicity Against HCMV After Lung Transplantation

The Journal of Infectious Diseases ◽

10.1093/infdis/jiaa097 ◽

2020 ◽

Vol 222 (3) ◽

pp. 417-427

Author(s):

Hannes Vietzen ◽

Irene Görzer ◽

Claudia Honsig ◽

Peter Jaksch ◽

Elisabeth Puchhammer-Stöckl

Keyword(s):

Human Cytomegalovirus ◽

Lung Transplant ◽

Enzyme Linked Immunosorbent Assay ◽

Transplant Recipients ◽

Antibody Dependent Cellular Cytotoxicity ◽

Specific Antibody Response ◽

Healthy Control ◽

Severe Infections ◽

Lung Transplant Recipients ◽

The Impact

Abstract Background Human cytomegalovirus (HCMV) may cause severe infections in lung transplant recipients (LTRs). The impact of the host antibody (AB)-dependent cytotoxicity (ADCC) on HCMV is still unclear. Therefore, we analyzed the AB-response against HCMV glycoprotein B (gB) and the pentameric complex (PC) and the ADCC response in HCMV-seropositive (R+) LTRs and in seronegative recipients of positive organs (D+/R−). Methods Plasma samples were collected from 35 R+ and 28 D+/R− LTRs for 1 (R+) or 2 (D+/R−) years posttransplantation and from 114 healthy control persons. The PC- and gB-specific ABs were assessed by enzyme-linked immunosorbent assay. The ADCC was analyzed by focal expansion assay and CD107 cytotoxicity assay. Results In R+ LTRs, significantly higher gB-specific AB levels developed within 1 year posttransplantation than in controls (immunoglobulin [Ig]G1, P < .001; IgG3, P < .001). In addition, higher levels of ADCC were observed by FEA and CD107 assay in R+ patients compared with controls (P < .001). In 23 D+R− patients, HCMV-specific ABs developed. Antibody-dependent cytotoxicity became detectable 3 months posttransplantation in these, with higher ADCC observed in viremic patients. Depletion of gB- and PC-specific ABs revealed that, in particular, gB-specific Abs were associated with the ADCC response. Conclusions We show that a strong ADCC is elicited after transplantation and is especially based on gB-specific ABs.

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Depression, Immunosuppressant Levels, and Clinical Outcomes in Postlung Transplant Recipients

The International Journal of Psychiatry in Medicine ◽

10.1177/0091217420906637 ◽

2020 ◽

Vol 55 (6) ◽

pp. 421-436 ◽

Cited By ~ 1

Author(s):

Michael C Chu ◽

Patrick J Smith ◽

John M Reynolds ◽

Scott M Palmer ◽

Laurie D Snyder ◽

...

Keyword(s):

Clinical Outcomes ◽

Lung Transplant ◽

Epidemiological Studies ◽

Hazard Ratio ◽

Adverse Outcomes ◽

Consecutive Series ◽

Transplant Recipients ◽

Increased Risk ◽

Coefficient Of Variability ◽

Lung Transplant Recipients

Objective Posttransplant depression has been linked to increased risk for adverse outcomes in lung transplant patients. Maintaining target serum immunosuppressant levels is also essential for optimal lung transplant clinical outcome and may be a crucial predictor of outcomes. Because depression could affect medication nonadherence, resulting in out-of-range immunosuppressant levels, we examined the relationship between posttransplant depression, immunosuppressant medication trough level variability, indexed by out-of-range values on clinical outcomes and coefficient of variability, and clinical outcomes. Method A consecutive series of 236 lung transplant recipients completed the Center for Epidemiological Studies-Depression two-month posttransplant. Immunosuppressant trough levels (i.e., tacrolimus or cyclosporine) within the range of individualized immunosuppressant targets were obtained at three-, six-, nine-month follow-up clinic visits. Clinical outcomes including hospitalizations and mortality were obtained from medical records. Results Fourteen percent of patients were classified as depressed (Center for Epidemiological Studies-Depression ≥16), 144 (61%) of patients had at least 25% out-of-range immunosuppressant values, and the average coefficient of variability was 36%. Over a median of 2.6 years (interquartile range = 1.2), 32 participants died (14%) and 144 (61%) had at least one unplanned, transplant-related hospitalization. Both depression (hazard ratio = 1.45 (1.19, 1.76), p < . 01) and immunosuppressant variation (immunosuppressant out-of-range: hazard ratio = 1.41 (1.10, 1.81), p < .01) independently predicted more frequent hospitalizations and higher mortality. Conclusions Early posttransplant depression was associated with significantly worse clinical outcomes. While immunosuppressant level variability is also related to adverse outcomes, such variability does not account for increased risk observed with depression.

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Assessment of Drug Resistance during Phase 2b Clinical Trials of Presatovir in Adults Naturally Infected with Respiratory Syncytial Virus

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02312-19 ◽

2020 ◽

Vol 64 (9) ◽

Cited By ~ 3

Author(s):

Danielle P. Porter ◽

Ying Guo ◽

Jason Perry ◽

David L. Gossage ◽

Timothy R. Watkins ◽

...

Keyword(s):

Drug Resistance ◽

Respiratory Syncytial Virus ◽

Clinical Outcomes ◽

Lung Transplant ◽

Fusion Inhibitor ◽

Transplant Recipients ◽

Genotypic Resistance ◽

Resistance Development ◽

Syncytial Virus ◽

Lung Transplant Recipients

ABSTRACT This study summarizes drug resistance analyses in 4 recent phase 2b trials of the respiratory syncytial virus (RSV) fusion inhibitor presatovir in naturally infected adults. Adult hematopoietic cell transplant (HCT) recipients, lung transplant recipients, or hospitalized patients with naturally acquired, laboratory-confirmed RSV infection were enrolled in 4 randomized, double-blind, placebo-controlled studies with study-specific presatovir dosing. Full-length RSV F sequences amplified from nasal swabs obtained at baseline and postbaseline were analyzed by population sequencing. Substitutions at RSV fusion inhibitor resistance-associated positions are reported. Genotypic analyses were performed on 233 presatovir-treated and 149 placebo-treated subjects. RSV F variant V127A was present in 8 subjects at baseline. Population sequencing detected treatment-emergent substitutions in 10/89 (11.2%) HCT recipients with upper and 6/29 (20.7%) with lower respiratory tract infection, 1/35 (2.9%) lung transplant recipients, and 1/80 (1.3%) hospitalized patients treated with presatovir; placebo-treated subjects had no emergent resistance-associated substitutions. Subjects with substitutions at resistance-associated positions had smaller decreases in viral load during treatment relative to those without, but they had similar clinical outcomes. Subject population type and dosing regimen may have influenced RSV resistance development during presatovir treatment. Subjects with genotypic resistance development had decreased virologic responses compared to those without genotypic resistance but had comparable clinical outcomes.

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