Precision and Personalized Medicine and anti-TB treatment:Is TDM feasible for programmatic use?

Therapeutic Drug Monitoring (TDM) is increasingly recommended to ensure the correct drug dose thereby minimizing adverse events and maximizing regimen efficacy. To facilitate implementation in TB programs, a framework for TDM is urgently needed. TDM is only useful for dose optimization if a patient is on an appropriate regimen guided by drug susceptibility testing. TDM using a targeted approach selecting patients with risk factors for suboptimal drug exposure (e.g. diabetes) or not responding to treatment for drugs with a clear concentration-response relationship may provide the best value for money. Semiquantitative point-of-care tests for detection of low or high drug concentration should be implemented at community level while quantitative assays can be performed at regional or central level. Expanding PK/PD research followed by clinical trials including both clinical outcome as well as cost-effectiveness will increase the level of evidence supporting TDM

Therapeutic drug monitoring of ganciclovir:Where are we?

Ganciclovir is the mainstay of therapy for the prophylaxis and treatment of Cytomegalovirus. However, therapy with this antiviral agent is hindered by side effects such as myelosuppression, which often leads to therapy cessation. Underdosing, as an attempt to prevent side effects, can lead to drug resistance and therapy failure. Therapeutic drug monitoring (TDM) has been used to overcome these problems. The purpose of this narrative review was to give an overview of ganciclovir TDM, available assays, population pharmacokinetic models, and discuss the current knowledge gaps. METHODS: For this narrative review, a nonsystematic literature search was performed on the PubMed database in April 2021. The following search terms were used: ganciclovir, valganciclovir, pharmacokinetics, pharmacodynamics, population pharmacokinetics, therapeutic drug monitoring, bioassay, liquid chromatography coupled with tandem mass spectrometry, liquid chromatography, chromatography, spectrophotometry, and toxicity. In addition, the reference lists of the included articles were screened. RESULTS: The most common bioanalysis method identified was liquid chromatography coupled with tandem mass spectrometry. There are different models presenting ganciclovir IC(50); however, establishing a pharmacokinetic/pharmacodynamic target for ganciclovir based on preclinical data is difficult because there are no studies combining dynamic drug exposure in relation to inhibition of viral replication. The data on ganciclovir TDM show large interindividual variability, indicating that TDM may play a role in modifying the dose to reduce toxicity and prevent treatment failure related to low concentrations. The main hurdle for implementing TDM is the lack of robust data to define a therapeutic window. CONCLUSIONS: Although the pharmacokinetics (PK) involved is relatively well-described, both the pharmacodynamics (PD) and pharmacokinetic/pharmacodynamic relationship are not. This is because the studies conducted to date have mainly focused on estimating ganciclovir exposure, and owing to the limited therapeutic options for CMV infections, future studies on ganciclovir are warranted

Personalised Medicine in the Treatment of Cancer

Understanding of pharmacokinetic-pharmacodynamic relationship for a given drug, and factors determining this, is an important part of personalised medicine in terms of choosing the correct regimen and maximising the therapeutic benefit with minimal toxicity. In the field of cancer, diversity of disease characteristics, complexity of regimens, as well as limited understanding of PK-PD profiles of rapidly-progressing anticancer drugs, create challenges for clinicians and patients to achieve the optimal outcome. This thesis addresses areas of cancer treatment where there is a need for identification of pharmacokinetic (PK), pharmacogenetic (PG) or physiological contributors, which may explain the observed variability, pharmacokinetics or toxicity of the studied drugs. The first component of the work aimed to investigate pharmacogenetic factors determining pharmacokinetics of actinomycin D. The study involves identification of the candidate transporters through in vitro uptake assays, which then led to clinical PK-PG analysis to determine clinically-significant transporter genotype influencing actinomycin D pharmacokinetics. The second component of the work explores pharmacodynamic associations between toxicity (pyrexia: body temperature > 38C) and exposure to dabrafenib and trametinib (CombiDT) used in the treatment of patients with melanoma expressing the common BRAF V600E/K mutation. A biomarker analysis using a panel of cytokines was also conducted to investigate their role in predicting or indicating the incidence of this toxicity. The significant findings of our study include identification of involvement of Solute Carrier (SLC) transporters (OAT4 and PEPT2) in actinomycin D uptake in vitro and the potentially predictive role of cytokines (IL-1B and IL-6) in CombiDT-induced pyrexia. Some of the results, such as the role of SLC transporters in clinical pharmacokinetics of actinomycin D in paediatric cancer patients, and drug exposure-pyrexia relationship for CombiDT treatment, lacked definitive conclusions due to study limitations, and provide areas of further research. Overall, we believe that our study has made valuable contributions to the enhanced understanding of these drugs, and a step closer to personalised medicine in the treatment of cancer

Saliva for Precision Dosing of Antifungal Drugs: Saliva Population PK Model for Voriconazole Based on a Systematic Review.

Precision dosing for many antifungal drugs is now recommended. Saliva sampling is considered as a non-invasive alternative to plasma sampling for therapeutic drug monitoring (TDM). However, there are currently no clinically validated saliva models available. The aim of this study is firstly, to conduct a systematic review to evaluate the evidence supporting saliva-based TDM for azoles, echinocandins, amphotericin B, and flucytosine. The second aim is to develop a saliva population pharmacokinetic (PK) model for eligible drugs, based on the evidence. Databases were searched up to July 2019 on PubMed® and Embase®, and 14 studies were included in the systematic review for fluconazole, voriconazole, itraconazole, and ketoconazole. No studies were identified for isavuconazole, posaconazole, flucytosine, amphotericin B, caspofungin, micafungin, or anidulafungin. Fluconazole and voriconazole demonstrated a good saliva penetration with an average S/P ratio of 1.21 (± 0.31) for fluconazole and 0.56 (± 0.18) for voriconazole, both with strong correlation (r = 0.89-0.98). Based on the evidence for TDM and available data, population PK analysis was performed on voriconazole using Nonlinear Mixed Effects Modeling (NONMEM 7.4). 137 voriconazole plasma and saliva concentrations from 11 patients (10 adults, 1 child) were obtained from the authors of the included study. Voriconazole pharmacokinetics was best described by one-compartment PK model with first-order absorption, parameterized by clearance of 4.56 L/h (36.9% CV), volume of distribution of 60.7 L, absorption rate constant of 0.858 (fixed), and bioavailability of 0.849. Kinetics of the voriconazole distribution from plasma to saliva was identical to the plasma kinetics, but the extent of distribution was lower, modeled by a scale factor of 0.5 (4% CV). A proportional error model best accounted for the residual variability. The visual and simulation-based model diagnostics confirmed a good predictive performance of the saliva model. The developed saliva model provides a promising framework to facilitate saliva-based precision dosing of voriconazole.status: publishe

Saliva for Precision Dosing of Antifungal Drugs: Saliva Population PK Model for Voriconazole Based on a Systematic Review.

Precision dosing for many antifungal drugs is now recommended. Saliva sampling is considered as a non-invasive alternative to plasma sampling for therapeutic drug monitoring (TDM). However, there are currently no clinically validated saliva models available. The aim of this study is firstly, to conduct a systematic review to evaluate the evidence supporting saliva-based TDM for azoles, echinocandins, amphotericin B, and flucytosine. The second aim is to develop a saliva population pharmacokinetic (PK) model for eligible drugs, based on the evidence. Databases were searched up to July 2019 on PubMed(R)and Embase(R), and 14 studies were included in the systematic review for fluconazole, voriconazole, itraconazole, and ketoconazole. No studies were identified for isavuconazole, posaconazole, flucytosine, amphotericin B, caspofungin, micafungin, or anidulafungin. Fluconazole and voriconazole demonstrated a good saliva penetration with an average S/P ratio of 1.21 (+/- 0.31) for fluconazole and 0.56 (+/- 0.18) for voriconazole, both with strong correlation (r = 0.89-0.98). Based on the evidence for TDM and available data, population PK analysis was performed on voriconazole using Nonlinear Mixed Effects Modeling (NONMEM 7.4). 137 voriconazole plasma and saliva concentrations from 11 patients (10 adults, 1 child) were obtained from the authors of the included study. Voriconazole pharmacokinetics was best described by one-compartment PK model with first-order absorption, parameterized by clearance of 4.56 L/h (36.9% CV), volume of distribution of 60.7 L, absorption rate constant of 0.858 (fixed), and bioavailability of 0.849. Kinetics of the voriconazole distribution from plasma to saliva was identical to the plasma kinetics, but the extent of distribution was lower, modeled by a scale factor of 0.5 (4% CV). A proportional error model best accounted for the residual variability. The visual and simulation-based model diagnostics confirmed a good predictive performance of the saliva model. The developed saliva model provides a promising framework to facilitate saliva-based precision dosing of voriconazole

Therapeutic drug monitoring of ganciclovir: Where are we?

PURPOSE: Ganciclovir is the mainstay of therapy for the prophylaxis and treatment of cytomegalovirus. However, therapy with this antiviral agent is hindered by side effects such as myelosuppression, which often leads to therapy cessation. Underdosing, as an attempt to prevent side effects, can lead to drug resistance and therapy failure. Therapeutic drug monitoring (TDM) has been used to overcome these problems. The purpose of this narrative review was to give an overview of ganciclovir TDM, available assays, population pharmacokinetic models and discuss the current knowledge gaps. METHODS: For this narrative review a non-systematic literature search was done on the PubMed database in April 2021. The following search terms were used: ganciclovir, valganciclovir, pharmacokinetics, pharmacodynamics, population pharmacokinetics, therapeutic drug monitoring, bioassay, LC-MS/MS, liquid chromatography, chromatography, spectrophotometry, toxicity. In addition, the reference lists of the included articles were screened. RESULTS: The most common bioanalysis method identified was liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). There are different models presenting ganciclovir IC50, however establishing a pharmacokinetic/pharmacodynamic (PK/PD) target for ganciclovir based on preclinical data is difficult, as there are no studies combining dynamic drug exposure in relation to inhibition of viral replication. The data on ganciclovir TDM show large inter-individual variability, indicating that TDM may play a role in modifying the dose to reduce toxicity and prevent treatment failure related to low concentrations. The main hurdle for implementing TDM is the lack of robust data to define a therapeutic window. CONCLUSION: Although the pharmacokinetics (PK) involved are relatively well-described, both the pharmacodynamics (PD) and PK/PD relationship are not. This is because the studies conducted to date have mainly focused on estimating ganciclovir exposure, and due to the limited therapeutic options for CMV infections, future studies on ganciclovir are warranted