Modelling changes in the pharmacokinetics of tacrolimus during pregnancy after kidney transplantation:A retrospective cohort study

Aims: Pregnancy after kidney transplantation is realistic but immunosuppressants should be continued to prevent rejection. Tacrolimus is safe during pregnancy and is routinely dosed based on whole-blood predose concentrations. However, maintaining these concentrations is complicated as physiological changes during pregnancy affect tacrolimus pharmacokinetics. The aim of this study was to describe tacrolimus pharmacokinetics throughout pregnancy and explain the changes by investigating covariates in a population pharmacokinetic model. Methods: Data of pregnant women using a twice-daily tacrolimus formulation following kidney transplantation were retrospectively collected from 6 months before conception, throughout gestation and up to 6 months postpartum. Pharmacokinetic analysis was performed using nonlinear mixed effects modelling. Demographic, clinical and genetic parameters were evaluated as covariates. The final model was evaluated using goodness-of-fit plots, visual predictive checks and a bootstrap analysis. Results: A total of 260 whole-blood tacrolimus predose concentrations from 14 pregnant kidney transplant recipients were included. Clearance increased during pregnancy from 34.5 to 41.7 L/h, by 15, 19 and 21% in the first, second and third trimester, respectively, compared to prior to pregnancy. This indicates a required increase in the tacrolimus dose by the same percentage to maintain the prepregnancy concentration. Haematocrit and gestational age were negatively correlated with tacrolimus clearance (P ≤ 0.01), explaining 18% of interindividual and 85% of interoccasion variability in oral clearance.Conclusions: Tacrolimus clearance increases during pregnancy, resulting in decreased exposure to tacrolimus, which is explained by gestational age and haematocrit. To maintain prepregnancy target whole-blood tacrolimus predose concentrations during pregnancy, increasing the dose is required.</p

Usage of Tacrolimus and Mycophenolic Acid During Conception, Pregnancy, and Lactation, and Its Implications for Therapeutic Drug Monitoring: A Systematic Critical Review

BACKGROUND: Conception, pregnancy, and lactation following solid organ transplantation require appropriate management. The most frequently used immunosu

Low Transfer of Tacrolimus and Its Metabolites into Colostrum of Graft Recipient Mothers

Currently, the majority of neonates born to organ recipient mothers on chronic immunosuppressive therapy are formula fed. However, over the past few years, evidence has grown, suggesting that breastfeeding might be possible and beneficial. We designed a study assessing the transfer of tacrolimus into the colostrum of posttransplant mothers. We assessed the amount of tacrolimus and its metabolites, M-1 and M-3, that would be ingested by the breastfed neonates. Concentrations of tacrolimus and its metabolites were measured in colostrum from 14 posttransplant mothers as well as in venous cord blood and venous blood of the neonates. Test material analysis was performed by liquid chromatography coupled with mass spectrometry (LC/MS). The amount of ingested formula was registered, which allowed for estimation of the amount of tacrolimus and its metabolites that would be ingested by breastfed infants. The mean amount of tacrolimus that would be ingested by the neonates in maternal milk was 151.4 ng/kg/24 h (standard deviation SD � 74.39); metabolite M-1: 23.80 ng/kg/24 h (SD � 14.53); and metabolite M-3: 13.25 ng/kg/24 h (SD � 9.05). The peak level of tacrolimus and metabolite M-1 in colostrum was noted 8 h after an oral dose (3.219 ng/mL SD � 2.22 and 0.56 ng/mL SD � 0.60, respectively) and metabolite M-3 after 6 h (0.29 ng/mL SD � 0.22). Low concentrations of tacrolimus and its metabolites, M-1 and M-3, in colostrum show that neonates will ingest trace amounts of the drug. Further studies are required to fully assess the safety of breastfeeding by posttransplant mothers

Usage of tacrolimus and mycophenolic acid during conception, pregnancy, and lactation, and its implications for therapeutic drug monitoring: a systematic critical review

Background: Conception, pregnancy, and lactation following solid organ transplantation require appropriate management. The most frequently used immunosuppressive drug combination after solid organ transplantation consists of tacrolimus (Tac) plus mycophenolic acid (MPA). Here, the effects of Tac and MPA on fertility, pregnancy, and lactation are systematically reviewed, and their implications for therapeutic drug monitoring (TDM) are discussed. Methods: A systematic literature search was performed (August 19, 2019) using Ovid MEDLINE, EMBASE, the Cochrane Central Register of controlled trials, Google Scholar, and Web of Science, and 102 studies were included. Another 60 were included from the reference list of the published articles. Results: As MPA is teratogenic, women who are trying to conceive are strongly recommended to switch from MPA to azathioprine. MPA treatment in men during conception seems to have no adverse effect on pregnancy outcomes. Nevertheless, in 2015, the drug label was updated with additional risk minimization measures in a pregnancy prevention program. Data on MPA pharmacokinetics during pregnancy and lactation are limited. Tac treatment during conception, pregnancy, and lactation seems to be safe in terms of the health of the mother, (unborn) child, and allograft. However, Tac may increase the risk of hypertension, preeclampsia, preterm birth, and low birth weight. Infants will ingest very small amounts of Tac via breast milk from mothers treated with Tac. However, no adverse outcomes have been reported in children exposed to Tac during lactation. During pregnancy, changes in Tac pharmacokinetics result in increased unbound to whole-blood Tac concentration ratio. To maintain Tac concentrations within the target range, increased Tac dose and intensified TDM may be required. However, it is unclear if dose adjustments during pregnancy are necessary, considering the higher concentration of (active) unbound Tac. Conclusions: Tac treatment during conception, pregnancy and lactation seems to be relatively safe. Due to pharmacokinetic changes during pregnancy, a higher Tac dose might be indicated to maintain target concentrations. However, more evidence is needed to make recommendations on both Tac dose adjustments and alternative matrices than whole-blood for TDM of Tac during pregnancy. MPA treatment in men during conception seems to have no adverse effect on pregnancy outcomes, whereas MPA use in women during conception and pregnancy is strongly discouraged.Personalised Therapeutic

the role of therapeutic drug monitoring and pharmacogenetic testing in the management of hiv infection a review

One of the less acknowledged tools in the international guidelines of combination antiretroviral therapy (cART) for HIV-1 infection is therapeutic drug monitoring (TDM). Yet anywhere there is a Clinical Pharmacology Unit or other facility for measuring plasma drug concentrations, physicians often measure the plasma levels of antiretrovirals as well as of comedications and find it useful. The aim of this article is to provide an overview of how relevant it is for a clinician to assess individual drug levels. Moreover we wanted to investigate to what extent the field is already assisted by web-based tools (i.e.: drug interaction charts). Finally we tried to look how pharmacogenetics may reduce the need for TDM, and whether this diagnostics is cost-effective. We searched PubMed by "drug interactions and HIV", "drug level and HIV", "therapeutic drug monitoring", and we investigated the Liverpool Drug Interaction website, the DHHS Guidelines website, the UCSF website, and the AETC online Guide for HIV/AIDS Clinical care. Furthermore, we assessed the role that the main national and international guidelines for antiretroviral treatment attributed to TDM and searched for the various clinical subsets in which drug monitoring is particularly relevant. Finally, we suggest that cross-sectional studies of subjects failing therapy or experiencing drug-related adverse events, as well as longitudinal studies of particular conditions, may show the importance of problem-targeted rather than routine TDM

A Joint Pharmacokinetic Model for the Simultaneous Description of Plasma and Whole Blood Tacrolimus Concentrations in Kidney and Lung Transplant Recipients

BACKGROUND AND OBJECTIVE: Historically, dosing of tacrolimus is guided by therapeutic drug monitoring (TDM) of the whole blood concentration, which is strongly influenced by haematocrit. The therapeutic and adverse effects are however expected to be driven by the unbound exposure, which could be better represented by measuring plasma concentrations.OBJECTIVE: We aimed to establish plasma concentration ranges reflecting whole blood concentrations within currently used target ranges.METHODS: Plasma and whole blood tacrolimus concentrations were determined in samples of transplant recipients included in the TransplantLines Biobank and Cohort Study. Targeted whole blood trough concentrations are 4-6 ng/mL and 7-10 ng/mL for kidney and lung transplant recipients, respectively. A population pharmacokinetic model was developed using non-linear mixed-effects modelling. Simulations were performed to infer plasma concentration ranges corresponding to whole blood target ranges.RESULTS: Plasma (n = 1973) and whole blood (n = 1961) tacrolimus concentrations were determined in 1060 transplant recipients. A one-compartment model with fixed first-order absorption and estimated first-order elimination characterised observed plasma concentrations. Plasma was linked to whole blood using a saturable binding equation (maximum binding 35.7 ng/mL, 95% confidence interval (CI) 31.0-40.4 ng/mL; dissociation constant 0.24 ng/mL, 95% CI 0.19-0.29 ng/mL). Model simulations indicate that patients within the whole blood target range are expected to have plasma concentrations (95% prediction interval) of 0.06-0.26 ng/mL and 0.10-0.93 ng/mL for kidney and lung transplant recipients, respectively.CONCLUSION: Whole blood tacrolimus target ranges, currently used to guide TDM, were translated to plasma concentration ranges of 0.06-0.26 ng/mL and 0.10-0.93 ng/mL for kidney and lung transplant recipients, respectively.</p

Individualized dosing algorithms for tacrolimus in kidney transplant recipients:current status and unmet needs

Introduction: Tacrolimus is a potent immunosuppressive drug with many side effects including nephrotoxicity and post-transplant diabetes mellitus. To limit its toxicity, therapeutic drug monitoring (TDM) is performed. However, tacrolimus’ pharmacokinetics are highly variable within and between individuals, which complicates their clinical management. Despite TDM, many kidney transplant recipients will experience under- or overexposure to tacrolimus. Therefore, dosing algorithms have been developed to limit the time a patient is exposed to off-target concentrations. Areas Covered: Tacrolimus starting dose algorithms and models for follow-up doses developed and/or tested since 2015, encompassing both adult and pediatric populations. Literature was searched in different databases, i.e. Embase, PubMed, Web of Science, Cochrane Register, and Google Scholar, from inception to February 2023 Expert Opinion: Many algorithms have been developed, but few have been prospectively evaluated. These performed better than bodyweight-based starting doses, regarding the time a patient is exposed to off-target tacrolimus concentrations. No benefit in reduced tacrolimus toxicity has yet been observed. Most algorithms were developed from small datasets, contained only a few tacrolimus concentrations per person, and were not externally validated. Moreover, other matrices should be considered which might better correlate with tacrolimus toxicity than the whole-blood concentration, e.g. unbound plasma or intra-lymphocytic tacrolimus concentrations.</p

A best-practice position statement on pregnancy after kidney transplantation: focusing on the unsolved questions. The Kidney and Pregnancy Study Group of the Italian Society of Nephrology

Kidney transplantation (KT) is often considered to be the method best able to restore fertility in a woman with chronic kidney disease (CKD). However, pregnancies in KT are not devoid of risks (in particular prematurity, small for gestational age babies, and the hypertensive disorders of pregnancy). An ideal profile of the potential KT mother includes “normal” or “good” kidney function (usually defined as glomerular filtration rate, GFR ≥ 60 ml/min), scant or no proteinuria (usually defined as below 500 mg/dl), normal or well controlled blood pressure (one drug only and no sign of end-organ damage), no recent acute rejection, good compliance and low-dose immunosuppression, without the use of potentially teratogen drugs (mycophenolic acid and m-Tor inhibitors) and an interval of at least 1–2 years after transplantation. In this setting, there is little if any risk of worsening of the kidney function. Less is known about how to manage “non-ideal” situations, such as a pregnancy a short time after KT, or one in the context of hypertension or a failing kidney. The aim of this position statement by the Kidney and Pregnancy Group of the Italian Society of Nephrology is to review the literature and discuss what is known about the clinical management of CKD after KT, with particular attention to women who start a pregnancy in non-ideal conditions. While the experience in such cases is limited, the risks of worsening the renal function are probably higher in cases with markedly reduced kidney function, and in the presence of proteinuria. Well-controlled hypertension alone seems less relevant for outcomes, even if its effect is probably multiplicative if combined with low GFR and proteinuria. As in other settings of kidney disease, superimposed preeclampsia (PE) is differently defined and this impairs calculating its real incidence. No specific difference between non-teratogen immunosuppressive drugs has been shown, but calcineurin inhibitors have been associated with foetal growth restriction and low birth weight. The clinical choices in cases at high risk for malformations or kidney function impairment (pregnancies under mycophenolic acid or with severe kidney-function impairment) require merging clinical and ethical approaches in which, beside the mother and child dyad, the grafted kidney is a crucial “third element”