Validation of a novel direct method to determine reduced adherence to atorvastatin therapy.

AIMS: Objective methods to determine statin adherence are requested to improve lipid management. We have recently established a method to detect reduced adherence to atorvastatin therapy with cut-off values based on the sum of atorvastatin and its major metabolites in blood. We aimed to validate this method in patients with and without cardiovascular disease, and optimize previous cut-off values. METHODS AND RESULTS: The pharmacokinetic study included 60 participants treated with atorvastatin 20 mg (N=20), 40 mg (N=20), and 80 mg (N=20). Atorvastatin was then stopped and blood samples collected from day zero to day four. Quantification of the parent drug and its metabolites in blood plasma was performed with a liquid chromatography-tandem mass spectrometry assay. The cut-off values for reduced adherence were validated and optimized by calculating diagnostic sensitivity and specificity. Our candidate cut-off value of dose-normalized six-component sum of atorvastatin plus metabolites <0.10 nM/mg provided a sensitivity of 97% and a specificity of 93% for detecting ≥2 omitted doses. An optimized cut-off <0.062 nM/mg provided a sensitivity of 90% and a specificity of 100%. An alternative simplified two-component metabolite sum with cut-off value <0.05 nM/mg provided a sensitivity of 98% and a specificity of 76%. An optimized cut-off <0.02 nM/mg provided a sensitivity of 97% and a specificity of 98%. CONCLUSION: This validation study confirms that our direct method discriminates reduced adherence from adherence to atorvastatin therapy with high diagnostic accuracy. The method may improve lipid management in clinical practice and serve as a useful tool in future studies.

The atorvastatin metabolite pattern in muscle tissue and blood plasma is associated with statin muscle side effects in patients with coronary heart disease; An exploratory case-control study.

Background and aims: Statin-associated muscle symptoms (SAMS) is a prevalent cause of statin discontinuation. It is challenging and time-consuming for clinicians to assess whether symptoms are caused by the statin or not, and diagnostic biomarkers are requested. Atorvastatin metabolites have been associated with SAMS. We aimed to compare atorvastatin pharmacokinetics between coronary heart disease (CHD) patients with and without clinically statin intolerance and statin-dependent histopathological alterations in muscle tissue. Secondarily we aimed to assess genetic variants relevant for the observed pharmacokinetic variables. Methods: Twenty-eight patients with CHD and subjective SAMS were included in the exploratory MUSE biomarker study in 2020. Participants received atorvastatin 40 mg/day for seven weeks followed by no statins for eight weeks. Muscle biopsies and blood were collected at the end of each period. Four patients were categorized as clinically intolerant to ≥3 statins prior to study start whereas four patients had signs of muscle cell damage during treatment. Results: We found significantly lower levels of atorvastatin acids, and higher lactone/acid ratios in the statin intolerant, both in muscle and plasma. With optimal cut-off, the combination of 2-OH-atorvastatin acid and the 2-OH-atorvastatin lactone/acid ratio provided sensitivity, specificity, and predictive values of 100 %. Patients with variants in UGT1A1 and UGT1A3 had higher lactone metabolite levels than those with wild type, both in muscle and plasma. Conclusion: Atorvastatin metabolites appear promising as biomarkers for the identification of clinical statin intolerance in patients with self-perceived SAMS, but the findings have to be confirmed in larger studies.

Clinical performance of volumetric finger-prick sampling for the monitoring of tacrolimus, creatinine and haemoglobin in kidney transplant recipients.

AIMS: Finger-prick sampling has emerged as an attractive tool for therapeutic drug monitoring and associated diagnostics. We aimed to validate the clinical performance of using two volumetric devices (Capitainer® qDBS and Mitra®) for monitoring tacrolimus, creatinine and haemoglobin in kidney transplant (KTx) recipients. Secondarily, we evaluated potential differences between finger-prick sampling performed by healthcare professionals vs. self-sampling, and differences between the two devices. METHODS: We compared finger-prick and venous sampling in three settings: microsampling performed by healthcare personnel, self-sampling under supervision, unsupervised self-sampling. The finger-prick samples were analysed with adapted methods and results compared to routine method analysis of the venous blood samples. RESULTS: Twenty-five KTx recipients completed the main study and 12 KTx recipients completed a post hoc validation study. For tacrolimus measurements and predicted area under the curve, the proportions within ±20% difference were 79%-96% for Capitainer and 77%-95% for Mitra. For creatinine and haemoglobin, the proportions within ±15% were 92%-100% and 93%-100% for Capitainer and 79%-96% and 67%-92% for Mitra, respectively. Comparing sampling situations, the success rate was consistent for Capitainer (92%-96%), whereas Mitra showed 72%-88% and 52%-72% success rates with samples collected by healthcare personnel and the patients themselves. CONCLUSIONS: Capitainer and Mitra are technically feasible for measuring tacrolimus, creatinine and haemoglobin. In the context of self-sampling, Capitainer maintained consistent sampling success and analytical quality. Implementing volumetric finger-prick self-sampling for the monitoring of tacrolimus, creatinine and haemoglobin may simplify and improve the follow-up of KTx recipients.

Atorvastatin Metabolite Pattern in Skeletal Muscle and Blood from Patients with Coronary Heart Disease and Statin-Associated Muscle Symptoms.

Self-perceived statin-associated muscle symptoms (SAMS) are prevalent, but only a minority is drug-dependent. Diagnostic biomarkers are not yet identified. The local statin exposure in skeletal muscle tissue may correlate to the adverse effects. We aimed to determine whether atorvastatin metabolites in blood reflect the corresponding metabolite levels in skeletal muscle, and whether genetic variants of statin transporters modulate this relationship. We also addressed atorvastatin metabolites as potential objective biomarkers of SAMS. Muscle symptoms were examined in patients with coronary disease and self-perceived SAMS during 7 weeks of double-blinded treatment with atorvastatin 40 mg/day and placebo in randomized order. A subset of 12 patients individually identified with more muscle symptoms on atorvastatin than placebo (confirmed SAMS) and 15 patients with no difference in muscle symptom intensity (non-SAMS) attended the present follow-up study. All received 7 weeks of treatment with atorvastatin 40 mg/day followed by 8 weeks without statins. Biopsies from the quadriceps muscle and blood plasma were collected after each treatment period. Strong correlations (rho > 0.7) between muscle and blood plasma concentrations were found for most atorvastatin metabolites. The impact of the SLCO1B1 c.521T>C (rs4149056) gene variant on atorvastatin's systemic pharmacokinetics was translated into muscle tissue. The SLCO2B1 c.395G>A (rs12422149) variant did not modulate the accumulation of atorvastatin metabolites in muscle tissue. Atorvastatin pharmacokinetics in patients with confirmed SAMS were not different from patients with non-SAMS. In conclusion, atorvastatin metabolite levels in skeletal muscle and plasma are strongly correlated, implying that plasma measurements are suitable proxies of atorvastatin exposure in muscle tissue. The relationship between atorvastatin metabolites in plasma and SAMS deserves further investigation.

Therapeutic Drug Monitoring and Dosage Adjustments of Immunosuppressive Drugs When Combined With Nirmatrelvir/Ritonavir in Patients With COVID-19.

ABSTRACT: Nirmatrelvir/ritonavir (Paxlovid) consists of a peptidomimetic inhibitor (nirmatrelvir) of the SARS-CoV-2 main protease and a pharmacokinetic enhancer (ritonavir). It is approved for the treatment of mild-to-moderate COVID-19. This combination of nirmatrelvir and ritonavir can mediate significant and complex drug-drug interactions (DDIs), primarily due to the ritonavir component. Indeed, ritonavir inhibits the metabolism of nirmatrelvir through cytochrome P450 3A (CYP3A) leading to higher plasma concentrations and a longer half-life of nirmatrelvir. Coadministration of nirmatrelvir/ritonavir with immunosuppressive drugs (ISDs) is particularly challenging given the major involvement of CYP3A in the metabolism of most of these drugs and their narrow therapeutic ranges. Exposure of ISDs will be drastically increased through the potent ritonavir-mediated inhibition of CYP3A, resulting in an increased risk of adverse drug reactions. Although a decrease in the dosage of ISDs can prevent toxicity, an inappropriate dosage regimen may also result in insufficient exposure and a risk of rejection. Here, we provide some general recommendations for therapeutic drug monitoring of ISDs and dosing recommendations when coadministered with nirmatrelvir/ritonavir. Particularly, tacrolimus should be discontinued, or patients should be given a microdose on day 1, whereas cyclosporine dosage should be reduced to 20% of the initial dosage during the antiviral treatment. Dosages of mammalian target of rapamycin inhibitors (m-TORis) should also be adjusted while dosages of mycophenolic acid and corticosteroids are expected to be less impacted.

Monitoring Simvastatin Adherence in Patients With Coronary Heart Disease: A Proof-of-Concept Study Based on Pharmacokinetic Measurements in Blood Plasma.

BACKGROUND: Poor statin adherence remains a public health concern associated with adverse outcomes. We evaluated the use of pharmacokinetic measurements to monitor adherence to simvastatin in patients with coronary heart disease (CHD). METHODS: Eighteen patients with CHD taking an evening dose of simvastatin 20 mg (n = 7), 40 mg (n = 5), or 80 mg (n = 6) were examined at steady-state pharmacokinetics. Ten patients were instructed to interrupt simvastatin dosing and return for blood sampling for the subsequent 3 days. Dose-normalized plasma concentrations of simvastatin lactone and simvastatin acid and the sum of the 2 were evaluated to discriminate between adherent dosing and dose omission. Bioanalytical quantification was performed using liquid chromatography-tandem mass spectrometry. RESULTS: A simvastatin acid cutoff of 1.0 × 10 -2 nmol -1 ·L -1 ·mg -1 identified 100% of those omitting 2 doses and 60% of those omitting a single dose. Simvastatin acid showed superior ability to discriminate dose omission, as well as the best agreement between samples handled at ambient and cool temperatures (median deviation 3.5%; interquartile range -2.5% to 13%). The cutoff for a morning dose schedule, with a similar ability to discriminate, was estimated at 2.0 × 10 -3 nmol -1 ·L -1 ·mg -1 . CONCLUSIONS: The present method discriminated between adherence and reduced adherence to simvastatin therapy in patients with CHD. Sample handling is feasible for routine practice, and the assessment of adherence can be performed by direct measurement of simvastatin acid in a blood sample, according to defined cutoff values. Further studies validating the cutoff value and utility for clinical application are encouraged.

Estimated glomerular filtration rate as a measurement of kidney function. / Estimert glomerulær filtrasjonshastighet som mål på nyrefunksjon.

Estimated glomerular filtration rate is an established, routine clinical measurement for kidney function, but the estimate has limitations and cannot be used in all clinical situations. Estimated glomerular filtration rate has a high coefficient of variation, and deviations in the patient's height, weight or muscle mass may result in an imprecise estimate. If an accurate measurement of kidney function is essential, glomerular filtration rate can be measured using an exogenous substance.

In vitro assessments predict that CYP3A4 contributes to a greater extent than CYP3A5 to prednisolone clearance.

Because several steroid hormones are metabolized to their respective 6ß-hydroxy forms by CYP3A4 and CYP3A5, these isoenzymes have been assumed to metabolize the immunosuppressive drug prednisolone, with conflicting results in the literature with respect to their relative importance. A direct study of the metabolism of prednisolone by microsomal CYP3A4 and CYP3A5 is missing. The aim of this in vitro study was to investigate the relative importance of recombinant CYP3A4 and recombinant CYP3A5 in the metabolism of prednisolone and to compare the extent of formation of 6ß-OH-prednisolone by the two enzymes. Through in vitro incubations using rCYP3A4 and rCYP3A5 enzymes, intrinsic clearance (CLint ) of prednisolone was determined by the substrate depletion approach. Formation of the metabolite 6ß-OH-prednisolone by rCYP3A4 and rCYP3A5, respectively, was compared. Prednisolone concentrations were measured, and its metabolite 6ß-OH-prednisolone was identified using a HPLC-MS/MS in-house method. CLint for prednisolone by rCYP3A5 was less than 26% relative to rCYP3A4. Formation of 6ß-OH-prednisolone by rCYP3A5 was less than 11% relative to rCYP3A4. The study indicates that 6ß-hydroxylation of prednisolone assessed in vitro in recombinant CYP enzymes depends on rCYP3A4 rather than rCYP3A5 and that CYP3A5 may be responsible for the formation of other prednisolone metabolite(s) in addition to 6ß-OH-prednisolone.

Fast and reliable quantification of busulfan in blood plasma using two-channel liquid chromatography tandem mass spectrometry: Validation of assay performance in the presence of drug formulation excipients.

A fast and reliable method based on two-channel liquid chromatography coupled to tandem mass spectrometry was developed and successfully validated for quantification of busulfan. The drug vehicle polyethylene glycol 400 was quantified simultaneously in patient samples. The sample preparation consisted of simple protein precipitation using a mixture of methanol and zinc sulphate containing busulfan-d8 as internal standard. Chromatographic separation was performed on a short biphenyl column (30 mm × 3.0 mm, 5 µm particles) using a step gradient from 30 % to 85 % methanol, ensuring co-elution of the analyte and internal standard. Quantification was performed using the mass transition of 264.1 > 151.1 for busulfan and 272.1 > 159.1 for the internal standard. Using only 20 µL of plasma sample, the lower limit of quantification was 25 ng/mL. Signal to noise ratio at the lower limit of quantification exceeded 300. The assay performance was not adversely affected by matrix effects originating from drug formulation excipients or other sample components. The coefficient of variation was ≤4 % and the mean accuracy 101-108 % across the calibration range 25-5 000 ng/mL. Chromatographic run time was 2 min and 8 s, allowing an effective run-time of 1 min and 10 s when using two alternating LC-channels. The assay has been implemented in routine practice with accreditation according to the ISO 15189 standard, and performs well in external quality control assessments. We present for the first time that shortly after an IV infusion of busulfan, the plasma levels of polyethylene glycol 400 may be in the range of 400-800 mg/L. The presence of these levels of detergent in patient samples may have detrimental effects on assay performance in LC-MS/MS, not limited to busulfan assays. This may be a concern for any LC-MS/MS analysis performed on samples collected within the first 24 h after an IV infusion of busulfan.

Personalized Therapy for Mycophenolate: Consensus Report by the International Association of Therapeutic Drug Monitoring and Clinical Toxicology.

ABSTRACT: When mycophenolic acid (MPA) was originally marketed for immunosuppressive therapy, fixed doses were recommended by the manufacturer. Awareness of the potential for a more personalized dosing has led to development of methods to estimate MPA area under the curve based on the measurement of drug concentrations in only a few samples. This approach is feasible in the clinical routine and has proven successful in terms of correlation with outcome. However, the search for superior correlates has continued, and numerous studies in search of biomarkers that could better predict the perfect dosage for the individual patient have been published. As it was considered timely for an updated and comprehensive presentation of consensus on the status for personalized treatment with MPA, this report was prepared following an initiative from members of the International Association of Therapeutic Drug Monitoring and Clinical Toxicology (IATDMCT). Topics included are the criteria for analytics, methods to estimate exposure including pharmacometrics, the potential influence of pharmacogenetics, development of biomarkers, and the practical aspects of implementation of target concentration intervention. For selected topics with sufficient evidence, such as the application of limited sampling strategies for MPA area under the curve, graded recommendations on target ranges are presented. To provide a comprehensive review, this report also includes updates on the status of potential biomarkers including those which may be promising but with a low level of evidence. In view of the fact that there are very few new immunosuppressive drugs under development for the transplant field, it is likely that MPA will continue to be prescribed on a large scale in the upcoming years. Discontinuation of therapy due to adverse effects is relatively common, increasing the risk for late rejections, which may contribute to graft loss. Therefore, the continued search for innovative methods to better personalize MPA dosage is warranted.

Tacrolimus Measured in Capillary Volumetric Microsamples in Pediatric Patients-A Cross-Validation Study.

BACKGROUND: Therapeutic drug monitoring of tacrolimus (Tac) is mandatory in solid organ transplant (SOT) recipients. Finger-prick microsampling is more flexible and tolerable during the therapeutic drug monitoring of tacrolimus and has been shown to be applicable in adult SOT recipients. In this study, a previously validated method applying volumetric absorptive microsampling (VAMS) to measure Tac in adults was cross-validated in a pediatric population. METHODS: Patients with SOT scheduled for standard posttransplant follow-up visits were recruited. Blood samples were obtained by trained phlebotomists using standard venipuncture and capillary microsampling, before the morning dose of Tac as well as 2 and 5 hours after dosing. Tac concentrations were quantified using liquid chromatography-tandem mass spectrometry. Concordance between Tac concentrations obtained with venipuncture and VAMS was evaluated using Passing-Bablok regression, calculation of absolute and relative differences, and percentage of samples within ±20% and ±30% difference. RESULTS: A total of 39 SOT patients aged 4-18 years (22 male) were included. The median (range) predose venous blood concentration was 4.8 (2.6-13.6) mcg/L, with a difference between VAMS and venous blood samples of -0.2 ± 0.7 mcg/L. The relative mean difference was -1.3% [95% confidence interval (CI), -5.9% to 3.4%]. Ninety-two percent and 97% of the sample pairs demonstrated differences within ±20% and ±30%, respectively. Postdose (2 hours and/or 5 hours, n = 17) median concentration in venous blood was 7.9 (4.8-19.2) mcg/L. The difference between VAMS and venous blood samples was 0.1 ± 1.0 mcg/L, with a relative mean difference of -2.5% (95% confidence interval, -8.8% to 3.8%). Eighty-eight percent of the postdose sample pairs were within ±20% difference, and all were within ±30% difference. CONCLUSIONS: Tac concentrations can be accurately measured using VAMS technology in pediatric SOT recipients. This makes home-based Tac monitoring feasible in the pediatric population.

Effect of atorvastatin on muscle symptoms in coronary heart disease patients with self-perceived statin muscle side effects: a randomized, double-blinded crossover trial.

AIMS: To estimate the effect of atorvastatin on muscle symptom intensity in coronary heart disease (CHD) patients with self-perceived statin-associated muscle symptoms (SAMS) and to determine the relationship to blood levels of atorvastatin and/or metabolites. METHODS AND RESULTS: A randomized multi-centre trial consecutively identified 982 patients with previous or ongoing atorvastatin treatment after a CHD event. Of these, 97 (9.9%) reported SAMS and 77 were randomized to 7-week double-blinded treatment with atorvastatin 40 mg/day and placebo in a crossover design. The primary outcome was the individual mean difference in muscle symptom intensity between the treatment periods, measured by visual-analogue scale (VAS) scores. Atorvastatin did not affect the intensity of muscle symptoms among 71 patients who completed the trial. Mean VAS difference (statin-placebo) was 0.31 (95% CI: -0.24 to 0.86). The proportion with more muscle symptoms during placebo than atorvastatin was 17% (n = 12), 55% (n = 39) had the same muscle symptom intensity during both treatment periods whereas 28% (n = 20) had more symptoms during atorvastatin than placebo (confirmed SAMS). There were no differences in clinical or pharmacogenetic characteristics between these groups. The levels of atorvastatin and/or metabolites did not correlate to muscle symptom intensity among patients with confirmed SAMS (Spearman's rho ≤0.40, for all variables). CONCLUSION: Re-challenge with high-intensity atorvastatin did not affect the intensity of muscle symptoms in CHD patients with self-perceived SAMS during previous atorvastatin therapy. There was no relationship between muscle symptoms and the systemic exposure to atorvastatin and/or its metabolites. The findings encourage an informed discussion to elucidate other causes of muscle complaints and continued statin use.

Prednisolone and Prednisone Pharmacokinetics in Adult Renal Transplant Recipients.

BACKGROUND: Prednisolone (PL) is a standard component of most immunosuppressive protocols after solid organ transplantation (Tx). Adverse effects are frequent and well known. The aim of this study was to characterize the pharmacokinetics (PKs) of PL and prednisone (PN), including cortisol (CL) and cortisone (CN) profiles, after PL treatment in renal Tx recipients in the early post-Tx phase. METHODS: This single-center, prospective, observational study included stable renal Tx recipients, >18 years of age, and in the early postengraftment phase. Blood samples were obtained predose and during a 24-hour dose interval [n = 26 samples per area under the curve (AUC0-24)], within the first 8 weeks post-Tx. PL, PN, CL, and CN concentrations were measured using high-performance liquid chromatography-tandem mass spectrometry. RESULTS: In renal Tx recipients (n = 28), our results indicated a relatively high PL exposure [median, range AUC0-24 = 3821 (2232-5382) mcg h/L], paralleled by strong suppression of endogenous CL profile, demonstrated by a low CL evening-to-morning ratio [median, range 11 (3-47)%]. A negative correlation (r = -0.83) between PL AUC0-24 and morning CL levels was observed. The best single PK variable to predict PL AUC0-24 was PL C6 (r2 = 0.82). An algorithm based on 3 PK sampling time points: trough, 2, and 4 hours after PL dosing, predicted PL AUC0-24 with a low percentage prediction error (PPE = 5.2 ± 1.5%) and a good correlation of determination (r2 = 0.91). PL AUC0-24 varied 3-fold among study participants, whereas CL AUC0-24 varied by 18-fold. CONCLUSIONS: The large interindividual variability in both PL exposure and suppression of endogenous CL implies a possible role for therapeutic drug monitoring. An abbreviated profile within the first 4 hours after PL dosing provides a good prediction of PL exposure in renal Tx recipients. The strong negative correlation between PL AUC0-24 and morning CL levels suggests a possible surrogate marker for drug exposure for further evaluation.

Fasting Status and Circadian Variation Must be Considered When Performing AUC-based Therapeutic Drug Monitoring of Tacrolimus in Renal Transplant Recipients.

Therapeutic drug monitoring (TDM) is mandatory for the immunosuppressive drug tacrolimus (Tac). For clinical applicability, TDM is performed using morning trough concentrations. With recent developments making tacrolimus concentration determination possible in capillary microsamples and Bayesian estimator predicted area under the concentration curve (AUC), AUC-guided TDM may now be clinically applicable. Tac circadian variation has, however, been reported, with lower systemic exposure following the evening dose. The aim of the present study was to investigate tacrolimus pharmacokinetic (PK) after morning and evening administrations of twice-daily tacrolimus in a real-life setting without restrictions regarding food and concomitant drug timing. Two 12 hour tacrolimus investigations were performed; after the morning dose and the following evening dose, respectively, in 31 renal transplant recipients early after transplantation both in a fasting-state and under real-life nonfasting conditions (14 patients repeated the investigation). We observed circadian variation under fasting-conditions: 45% higher peak-concentration and 20% higher AUC following the morning dose. In the real-life nonfasting setting, the PK-profiles were flat but comparable after the morning and evening doses, showing slower absorption rate and lower AUC compared with the fasting-state. Limited sampling strategies using concentrations at 0, 1, and 3 hours predicted AUC after fasting morning administration, and samples obtained at 1, 3, and 6 hours predicted AUC for the other conditions (evening and real-life nonfasting). In conclusion, circadian variation of tacrolimus is present when performed in patients who are in the fasting-state, whereas flatter PK-profiles and no circadian variation was present in a real-life, nonfasting setting.

Measuring Intracellular Concentrations of Calcineurin Inhibitors: Expert Consensus from the International Association of Therapeutic Drug Monitoring and Clinical Toxicology Expert Panel.

BACKGROUND: Therapeutic drug monitoring (TDM) of the 2 calcineurin inhibitors (CNIs), tacrolimus (TAC) and cyclosporin A, has resulted in improvements in the management of patients who have undergone solid organ transplantation. As a result of TDM, acute rejection (AR) rates and treatment-related toxicities have been reduced. Irrespective, AR and toxicity still occur in patients who have undergone transplantation, showing blood CNI concentrations within the therapeutic range. Moreover, the AR rate is no longer decreasing. Hence, smarter TDM approaches are necessary. Because CNIs exert their action inside T lymphocytes, intracellular CNIs may be a promising candidate for improving therapeutic outcomes. The intracellular CNI concentration may be more directly related to the drug effect and has been favorably compared with the standard, whole-blood TDM for TAC in liver transplant recipients. However, measuring intracellular CNIs concentrations is not without pitfalls at both the preanalytical and analytical stages, and standardization seems essential in this area. To date, there are no guidelines for the TDM of intracellular CNI concentrations. METHODS: Under the auspices of the International Association of TDM and Clinical Toxicology and its Immunosuppressive Drug committees, a group of leading investigators in this field have shared experiences and have presented preanalytical and analytical recommendations for measuring intracellular CNI concentrations.

Pharmacologic Treatment of Transplant Recipients Infected With SARS-CoV-2: Considerations Regarding Therapeutic Drug Monitoring and Drug-Drug Interactions.

BACKGROUND: COVID-19 is a novel infectious disease caused by the severe acute respiratory distress (SARS)-coronavirus-2 (SARS-CoV-2). Several therapeutic options are currently emerging but none with universal consensus or proven efficacy. Solid organ transplant recipients are perceived to be at increased risk of severe COVID-19 because of their immunosuppressed conditions due to chronic use of immunosuppressive drugs (ISDs). It is therefore likely that solid organ transplant recipients will be treated with these experimental antivirals. METHODS: This article is not intended to provide a systematic literature review on investigational treatments tested against COVID-19; rather, the authors aim to provide recommendations for therapeutic drug monitoring of ISDs in transplant recipients infected with SARS-CoV-2 based on a review of existing data in the literature. RESULTS: Management of drug-drug interactions between investigational anti-SARS-CoV-2 drugs and immunosuppressants is a complex task for the clinician. Adequate immunosuppression is necessary to prevent graft rejection while, if critically ill, the patient may benefit from pharmacotherapeutic interventions directed at limiting SARS-CoV-2 viral replication. Maintaining ISD concentrations within the desired therapeutic range requires a highly individualized approach that is complicated by the pandemic context and lack of hindsight. CONCLUSIONS: With this article, the authors inform the clinician about the potential interactions of experimental COVID-19 treatments with ISDs used in transplantation. Recommendations regarding therapeutic drug monitoring and dose adjustments in the context of COVID-19 are provided.

Measured GFR by Utilizing Population Pharmacokinetic Methods to Determine Iohexol Clearance.

INTRODUCTION: There is an increasing demand for accurately measured glomerular filtration rate (GFR). Iohexol serum clearance has become a new gold standard, but it is challenging when GFR is low and 24-hour sampling is required for accurate results. The primary aim of this study was to develop an iohexol pharmacokinetic population model for accurate determination of individual GFR using limited sampling for up to 5 hours also when renal function is <40 ml/min. METHODS: A nonparametric iohexol population pharmacokinetic model was developed with rich data from 176 patients. In a validation cohort of 43 patients, a model-determined GFR (iohexol clearance) using different limited sampling strategies for up to 5 hours was compared with the strategy currently used in routine care, a log-linear 2-point method. In all, 1526 iohexol concentrations were used, from patients ranging in age from 1 to 82 years and GFR from 14 to 149 ml/min. RESULTS: The clinical 2-point method showed insufficient agreement compared with reference values; 15% of GFR values had an error of greater than ±10% even when sampling for 24 hours when estimating GFR <40 ml/min per 1.73 m2 (standard procedure). Restricted sampling the first 5 hours with the population model required 4 samples to determine GFR accurately. This strategy showed excellent agreement with the reference; <3% of GFR values had an error greater than ±10 %. CONCLUSION: Using an iohexol population pharmacokinetic model allows for accurate determination of GFR within 5 hours when applying 4 optimally timed samples, even in patients with GFR <40 ml/min.