Application of Physiologically Based Pharmacokinetic Modeling to Predict Drug-Drug Interactions between Elexacaftor/Tezacaftor/Ivacaftor and Tacrolimus in Lung Transplant Recipients.

Elexacaftor/tezacaftor/ivacaftor (ETI) treatment has potential benefits in lung transplant recipients, including improvements in extrapulmonary manifestations, such as gastrointestinal and sinus disease; however, ivacaftor is an inhibitor of cytochrome P450 3A (CYP3A) and may, therefore, pose a risk for elevated systemic exposure to tacrolimus. The aim of this investigation is to determine the impact of ETI on tacrolimus exposure and devise an appropriate dosing regimen to manage the risk of this drug-drug interaction (DDI). The CYP3A-mediated DDI of ivacaftor-tacrolimus was evaluated using a physiologically based pharmacokinetic (PBPK) modeling approach, incorporating CYP3A4 inhibition parameters of ivacaftor and in vitro enzyme kinetic parameters of tacrolimus. To further support the findings in PBPK modeling, we present a case series of lung transplant patients who received both ETI and tacrolimus. We predicted a 2.36-fold increase in tacrolimus exposure when co-administered with ivacaftor, which would require a 50% dose reduction of tacrolimus upon initiation of ETI treatment to avoid the risk of elevated systemic exposure. Clinical cases (N = 13) indicate a median 32% (IQR: -14.30, 63.80) increase in the dose-normalized tacrolimus trough level (trough concentration/weight-normalized daily dose) after starting ETI. These results indicate that the concomitant administration of tacrolimus and ETI may lead to a clinically significant DDI, requiring the dose adjustment of tacrolimus.

Comparison of Skin Cancer Incidence in Caucasian and Non-Caucasian Liver Vs. Lung Transplant Recipients: A Tale of Two Regimens.

BACKGROUND: Organ transplantation is a significant risk factor for the development of skin cancer. The impact of skin type, immunosuppressive regimens, and photosensitizing agents requires further study. OBJECTIVE: The objective of this study was to compare skin cancer development between Caucasian and non-Caucasian transplant recipients at the University of Southern California. METHODS: We performed a retrospective chart review of lung and liver transplantations to determine the incidence of post-transplant skin cancer. Participants included patients who underwent lung or liver transplantation between 2005 and 2013 at our institution. Patients included in the study were limited to those who survived through the study observation period. RESULTS: We analyzed 475 patients who underwent transplantation, including 370 liver transplant recipients and 105 lung transplant recipients. Among these, 46.3% identified as Caucasian, while 53.7% were non-Caucasian. Over a mean follow-up of 7.9 years, 11.8% of Caucasian patients developed at least one skin cancer, compared with 2.7% of non-Caucasians (p < 0.001). However, irrespective of race, skin cancer development was significantly greater in lung compared with liver transplant recipients (20.0% vs. 3.2%, p < 0.001). The standard immunosuppressive and prophylactic regimens were mycophenolate mofetil and tacrolimus based for both transplants. Mycophenolate mofetil was maintained throughout the course in lung transplant patients, whereas this agent was reduced and terminated when possible in liver transplant recipients. In addition, during the years examined, voriconazole, a known photosensitizing agent, was used in lung transplant recipients to prevent aspergillosis. CONCLUSIONS: Fair skin type increases post-transplant skin cancer development, irrespective of the immunosuppressive regimen. A higher risk of skin cancer is associated with different regimens; in particular photosensitizing agents may increase risk in transplant recipients.

Use of Foscarnet Therapy for EBV Infection following Control of PTLD with Enhancement of Cellular Immunity in a Lung-Transplant Recipient.

Posttransplant lymphoproliferative disorder (PTLD) is a serious complication following solid organ transplantation with an annual incidence rate of 3-5% in lung-transplant recipients. Pathogenesis indicates a strong association with functional over-immunosuppression and EBV infection. Clinical improvement is generally observed with reduction in immunosuppression intensity alone. We present a case of a 24-year-old woman with EBV-associated PTLD following lung transplant where decreasing the immunosuppression improved PTLD but was ineffective against controlling the EBV infection. Foscarnet in combination with immunoglobulins was successfully administered to cause a remission of the EBV infection. This is the second case reported of a persistent EBV infection after reducing immunosuppression levels and evidence of PTLD remission that required foscarnet for EBV infection control.

Endothelial dysfunction and decreased vascular responsiveness in the anterior cruciate ligament-deficient model of osteoarthritis.

Chronic inflammation associated with osteoarthritis (OA) may alter normal vascular responses and contribute to joint degradation. Vascular responses to vasoactive mediators were evaluated in the medial collateral ligament (MCL) of the anterior cruciate ligament (ACL)-deficient knee. Chronic joint instability and progressive OA were induced in rabbit knees by surgical transection of the ACL. Under halothane anesthesia, laser speckle perfusion imaging (LSPI) was used to measure MCL blood flow in unoperated control (n = 12) and 6-wk ACL-transected knees (n = 12). ACh, bradykinin, histamine, substance P (SP), and prostaglandin E(2) (PGE(2)) were applied to the MCL vasculature in topical boluses of 100 microl (dose range 10(-14) to 10(-8) mol). In normal joints, ACh, bradykinin, histamine, and PGE(2) evoked a dilatory response. Substance P caused a biphasic response that was dilatory from 10(-14) to 10(-11) mol and constricting at higher doses. In ACL-deficient knees, ACh, bradykinin, histamine, and SP decreased perfusion, whereas PGE(2) had a biphasic response that decreased perfusion at 10(-14) to 10(-11) mol and was dilatory at higher concentrations. Sodium nitroprusside increased perfusion in resting and phenylephrine-precontracted vessels with no significant differences between ACL-transected and control knees. Femoral artery occlusion and release increased perfusion by 74.3 +/- 11.1% in control knees but only by 25.8 +/- 4.4% in ACL-deficient knees. The altered responsiveness of the MCL vasculature to these inflammatory mediators may indicate endothelial dysfunction in the MCL, which may contribute to the progression and severity of OA and to the adaptation of the joint in an altered mechanical environment.

ACL deficiency impairs the vasoconstrictive efficacy of neuropeptide Y and phenylephrine in articular tissues: a laser speckle perfusion imaging study.

Sympathetic-derived neuropeptide Y (NPY) helps regulate inflammatory responses in injury and disease, is a vasoconstrictor, and stimulates angiogenesis. Rupture of the anterior cruciate ligament (ACL) is a common clinical presentation that results in tissue inflammation, hyperemia, and angiogenesis in the intact medial collateral ligament (MCL). This study is the first to examine the vasoregulatory role of NPY in ACL-deficient knee joints by using the newly developed technique of laser speckle perfusion imaging (LSPI). MCL blood flow was measured in two groups of adult rabbits: unoperated control (n = 6), and 6-wk ACL transected (n = 5). Under anesthesia, the MCL was surgically exposed and tissue blood flow was imaged at high resolution using LSPI. NPY was applied to the MCL vasculature in topical boluses of 100 mul (dose range 10(-14) to 10(-9) mol), and the alpha-adrenoceptor agonist phenylephrine was applied in doses of 10(-14), 10(-10), and 10(-7) mol. In control rabbits, topical administration of NPY or phenylephrine produced dose-dependent vasopressor responses (maximal effect at 10(-9) mol NPY and 10(-7) mol phenylephrine). In ACL-transected knees, there was little or no vasoconstrictive response to NPY at any dose. The response to phenylephrine was significantly reduced compared with control ligaments. Possible causes of the reduced vasoconstrictive response to NPY in the MCL after 6 wk of ACL deficiency include development of tolerance to the peptide due to a prolonged increase in sympathetic nerve activity or change in the distribution or functionality of the NPY Y(1) receptors. Chronic ACL deficiency leads to profound and protracted hyperemia in associated articular tissues. Abrogation of a vasoconstrictor response to both NPY and phenylephrine in the MCL indicates that ACL deficiency induces major changes in the vascular physiological homeostasis.

A laser speckle imaging technique for measuring tissue perfusion.

Laser Doppler imaging (LDI) has become a standard method for optical measurement of tissue perfusion, but is limited by low resolution and long measurement times. We have developed an analysis technique based on a laser speckle imaging method that generates rapid, high-resolution perfusion images. We have called it laser speckle perfusion imaging (LSPI). This paper investigates LSPI output and compares it to LDI using blood flow models designed to simulate human skin at various levels of pigmentation. Results show that LSPI parameters can be chosen such that the instrumentation exhibits a similar response to changes in red blood cell concentration (0.1%-5%, 200 microL/min) and velocity (0-800 microL/min, 1% concentration) and, given its higher resolution and quicker response time, could provide a significant advantage over LDI for some applications. Differences were observed in the LDI and LSPI response to tissue optical properties. LDI perfusion values increased with increasing tissue absorption, while LSPI perfusion values showed a slight decrease. This dependence is predictable, owing to the perfusion algorithms specific to each instrument, and, if properly compensated for, should not influence each instrument's ability to measure relative changes in tissue perfusion.

Laser Doppler imaging of burn scars: a comparison of wavelength and scanning methods.

UNLABELLED: Laser Doppler perfusion imaging (LDI) is a useful tool for the early clinical assessment of burn depth and prognostic evaluation of injuries that may require skin grafting. We have evaluated two commercially available laser Doppler imagers for the perfusion measurement of normal and burn scar tissue. METHODS: A single wavelength (635 nm), step-wise scanning LDI and a dual wavelength (633 and 780 nm), continuous scanning LDI were used. Twenty patients with hypertrophic burn scars (time since injury: 1 month-8 years) were recruited and the color and elevation of the scar was clinically assessed using a modified Vancouver Burn Scar Scale. Perfusion of each scar region was measured using both imagers. A symmetric contralateral region of unburned skin was also imaged to record baseline perfusion. RESULTS: Comparisons of wavelength and scanning technique were made using perfusion values obtained from 22 burn scars. Highly significant positive correlation was observed in all comparisons. In addition, output from both instruments was strongly and significantly correlated with the clinical grading of the scar. SIGNIFICANCE: Both LDI scanners perform similar perfusion measurements. The results also indicate that red and near-infrared (NIR) wavelength photons provide similar blood flow information. The faster, continuous scanning method provides a clinical advantage without a significant loss of blood flow information. However, a critical evaluation of both instruments suggests that caution must be exercised when using these optical diagnostic techniques and that some knowledge of light-tissue interaction is required for the proper analysis and interpretation of clinical data.