Maximum Recommended Dosage of Lithium for Pregnant Women Based on a PBPK Model for Lithium Absorption

Treatment of bipolar disorder with lithium therapy during pregnancy is a medical challenge. Bipolar disorder is more prevalent in women and its onset is often concurrent with peak reproductive age. Treatment typically involves administration of the element lithium, which has been classified as a class D drug (legal to use during pregnancy, but may cause birth defects) and is one of only thirty known teratogenic drugs. There is no clear recommendation in the literature on the maximum acceptable dosage regimen for pregnant, bipolar women. We recommend a maximum dosage regimen based on a physiologically based pharmacokinetic (PBPK) model. The model simulates the concentration of lithium in the organs and tissues of a pregnant woman and her fetus. First, we modeled time-dependent lithium concentration profiles resulting from lithium therapy known to have caused birth defects. Next, we identified maximum and average fetal lithium concentrations during treatment. Then, we developed a lithium therapy regimen to maximize the concentration of lithium in the mother's brain, while maintaining the fetal concentration low enough to reduce the risk of birth defects. This maximum dosage regimen suggested by the model was 400 mg lithium three times per day

Perchlorates

prepared by Syracuse Research Corporation ; prepared for U.S. Department of Health and Human Services, Public Health Service, Agency for Toxic Substances and Disease Registry."August 2008."Chemical manager(s)/author(s): Sharon Wilbur, ATSDR, Division of Toxicology and Environmental Medicine; Gary Diamond, Fernando Llados, Marc Odin, Daniel Plewak, Jay Tunkel, Syracuse Research Corporation. --P. ix."Under contract no. 200-2004-09793."Also available via the World Wide Web.Includes bibliographical references (p. 217-250) and index

Optimization of buprenorphine dosing in pregnant women

The primary objective of this work was to optimize buprenorphine (BUP) dosing based on exposure in treating opioid addiction in pregnant women. A combination of clinical pharmacokinetic study and modeling and simulation was used to accomplish this. The clinical study evaluated BUP pharmacokinetics (PK) during pregnancy and postpartum. Up to 3 studies were performed in each participant during 1st-, 2nd -half of pregnancy, and postpartum. At each study visit, multiple blood samples and specific pharmacodynamics measurements were collected. Plasma concentrations of BUP were quantified using UPLC-MS/MS. In this study BUP exposure was lower during pregnancy compared to postpartum. A physiologically-based pharmacokinetic (PBPK) model of intravenous and sublingual BUP was developed and verified using 14 independent BUP PK studies. This PBPK model predicted decreased BUP exposure during pregnancy compared to postpartum, consistent with the observations from the clinical study. Non-linear mixed effects modeling using a first-order conditional estimation with interaction to analyze changes in BUP PK in pregnant women was conducted. Buprenorphine PK data were well-characterized by a two-compartment model with first-order absorption with enterohepatic recirculation and first-order elimination. The model estimated population apparent clearance (CL/F) of BUP in a typical pregnant woman was 469 L/h. Pregnancy was associated with a 1.64 folds increase in CL/F of BUP compared to postpartum period. A pharmacodynamic (PD) analysis showed that the average area under curves of COWS scores during pregnancy were significantly greater than postpartum period following administration of BUP, which is consistent with the v observed lower buprenorphine exposure during pregnancy. The relationship between pupillary diameters and BUP concentration was described by a sigmoidal Emax model with a hypothetical effect compartment. The calculated IC50 of BUP concentration for pupillary diameter changes was not significantly different during pregnant and postpartum, suggesting that there may not be any significant change in the sensitivity and /or number of µ-opioid receptors in the brain in pregnant women compared to non-pregnant women. Overall, the clinical observations and the two different modeling approaches demonstrated that BUP exposure is decreased during pregnancy and this alteration in BUP exposure is associated a decreased response to BUP in pregnancy

Mood stabilizers in pregnancy and lactation

Abstract Management of bipolar during pregnancy and postpartum is very challenging. The treating clinicians have to take into account various factors like current mental state, longitudinal history of the patient, past history of relapse while off medication, response to medication, time of pregnancy at which patient presents to the clinician, etc. The choice of drug should depend on the balance between safety and efficacy profile. Whenever patient is on psychotropic medication, close and intensive monitoring should be done. Among the various mood stabilizers, use of lithium during the second and third trimester appears to be safe. Use of valproate during first trimester is associated with major malformation and long-term sequalae in the form of developmental delay, lower intelligence quotient, and higher risk of development of autism spectrum disorder. Similarly use of carbamazepine in first trimester is associated with higher risk of major congenital malformation and its use in first trimester is contraindicated. Data for lamotrigine (LTG) appears to be more favorable than other antiepileptics. During lactation, use of valproate and LTG is reported to be safe. Use of typical and/atypical antipsychotic is a good option during pregnancy in women with bipolar disorder

OPTIMIZATION OF MYCOPHENOLATE MOFETIL DOSING IN TRANSPLANT PATIENTS

Mycophenolate Mofetil (MMF) is an immunosuppressive pro-drug of mycophenolic acid (MPA), first approved by the US Food and Drug Administration (FDA) in 1995 for the prevention of rejection post solid organ transplantation (SOT). A narrow therapeutic index, poor predictability of exposure from trough drug level monitoring, large inter transplant as well as inter and intra subject variability and lack of guidelines for optimal dosing are the primary reasons that make it very crucial to apply pharmacokinetic (PK) and pharmacodynamic (PD) concepts to individualize the dosing of MPA in transplant sub-populations. A target range of the active form, MPA measured by the area under the concentration time curve (AUC) in renal transplant recipients of 30-60 mg*h/L has been shown to be associated with better graft and overall survival. This work attempts at optimizing dosing of MMF in pediatric HSCT recipients and in adult lung transplant recipients by using different dosing regimens, therapeutic drug monitoring and modeling approaches. We evaluated the safety and feasibility of a personalized pharmacokinetics-based dosing approach in pediatric HSCT patients using a novel continuous infusion (CI) method of administration of MMF to improve MPA exposure. We further evaluated the feasibility of a PK and PD focused dosing of MMF in adult lung transplant (LT) recipients. Total plasma concentrations of MPA measured by a UPLC-MS assay were inversely related to the inosine-5′-monophosphate dehydrogenase (IMPDH) activity, with the lowest activity being seen at the maximum MPA concentration. In a pilot study conducted in LT recipients, although statistically not significant, the pre-dose IMPDH activity at the bronchoscopy visit tended to be higher in patients who rejected compared to those who did not have any rejection episodes. Finally, a robust physiologically based pharmacokinetic (PBPK) model of MPA was built and validated in healthy Caucasian and Chinese volunteers, pediatric patients, kidney transplant recipients and patients with varying degree of renal impairment with an intent to apply this in clinical practice to lung and pediatric HSCT patients. The promising results from this work can serve as the foundation for future studies optimizing the use of MPA in transplant patients

The Future of Teratology Research is In Vitro

Birth defects induced by maternal exposure to exogenous agents during pregnancy are preventable, if the agents themselves can be identified and avoided. Billions of dollars and manhours have been dedicated to animal-based discovery and characterisation methods over decades. We show here, via a comprehensive systematic review and analysis of this data, that these methods constitute questionable science and pose a hazard to humans. Mean positive and negative predictivities barely exceed 50%; discordance among the species used is substantial; reliable extrapolation from animal data to humans is impossible, and virtually all known human teratogens have so far been identified in spite of, rather than because of, animal-based methods. Despite strict validation criteria that animal-based teratology studies would fail to meet, three in vitro alternatives have done so. The embryonic stem-cell test (EST) is the best of these. We argue that the poor performance of animalbased teratology alone warrants its cessation; it ought to be replaced by the easier, cheaper and more repeatable EST, and resources made available to improve this and other tests even further

Prevention of Organ-Specific Doxorubicin Induced Toxicity Using Physiologically-Based Pharmacokinetic Modeling and Therapeutic Drug Monitoring

Physiology-based pharmacokinetic models are mathematical models that characterize the behavior of a drug and have compartmental equations that are representative of specific tissues and physiological processes.[1, 2] Doxorubicin is an anthracycline antibiotic that is effective and widely used in anticancer therapy due to its potent cytotoxicity. Unfortunately, with that potency comes cardiotoxic side effects related to cumulative lifetime dose.[3] Specifically, the toxicity is related to the accumulation of the primary metabolite doxorubicinol (DOXol) in the heart.[4] Since the toxicity is organ-specific, the best way to characterize the behavior is through PBPK modeling.[2] Since PBPK models tend to be large systems of ODEs, several numerical methods were attempted for solving the model before a matrix-based approach was chosen.[5, 6] The eigenvalue/eigenvector solution was evaluated at three time points which were then included in a Composite Simpson’s Rule numerical integration for the length of some time interval.[5, 7] The PBPK model, adapted from a pig model, was fit to mouse data and scaled to predict rat, rabbit, dog, pig, and human data sets using an allometric scaling equation on the blood:plasma partition coefficient B : P .[8, 9, 10] Despite extensive investigation into dose adjustments for DOX, no covariates were consistently found to improve the efficacy and minimize toxicity except dosing schedule – infusion rate and duration.[11] The criterion for decreasing incidence of cardiotoxicity was maintaining a sub-toxic Cmax,heart,DOXol in the heart while maximizing exposure, represented by area under the concentration-time-curve (AUC). Thus, the original mouse data set was ideal since it included both DOX venous blood concentration and DOXol heart concentration.[12] The model was optimized at 10 time points between 1 minute and 72 hours with the goal of (AUC) maximization without exceeding Cmax,heart,DOXol. Using these predictions, therapeutic drug monitoring could be executed by taking the plasma concentration samples during a patient’s first DOX dose, PBPK model predictions could provide AUC and Cmax,heart,DOXol data, which could then inform the infusion parameters for the next dose. Clinical thresholds for Cmax,vb have been established for incidence of adverse effects, and in future work, perhaps a similar threshold for cardiotoxicity could also be established using tissue-specific measures

Optimising Therapeutic Outcomes in CNS Disorders: Pharmaceutical and Pharmacokinetic Approaches

Central nervous system (CNS) disorders have been highlighted by the World Health Organisation (WHO) as one of the biggest threats to public health. This study aimed to improve the clinical outcomes in CNS disorders, with focus on major depression, through pharmaceutical and pharmacokinetic approaches by the use of transdermal base creams and patches for the delivery of a phytochemical and the use of in-silico modelling to optimise antidepressant dosing in challenging populations such as pregnant women. The flavonoid hesperetin, as a potential candidate for CNS disorders, was incorporated into commercial base creams (Vanish-Pen™, Doublebase™ gel, Versatile™, and Pentravan®). In-vitro drug release studies were conducted at week 0 showing that Pentravan® formulation released the highest percentage of hesperetin (12.69 % (0.68 %)), while Versatile™ released the lowest (4.53 % (0.65 %)). Storage studies on Vanish-pen™ and Doublebase™ were consistent for 10 weeks when stored at 4°C and 25°C, respectively, while Versatile™ showed consistent profiles when stored at both 4°C and 25°C. Significant changes were detected in the release profiles of Pentravan® during storage at both temperatures. Transdermal hesperetin patch systems were developed using either Dow Corning® BIO-PSA 7-4501 silicone adhesive or Eudragit® E100 acrylic adhesive. The silicone-based patch that contains 5.5 % glycerol provided the highest release, 39.9 % (0.37 %), but during storage for 3 weeks at 4°C and 25°C, the release significantly decreased. The Eudragit®-based patch that produced the highest release (8 % (0.06 %)) was composed of 5% glycerol and 45% of triacetin. However, during storage the acrylic-based patches degraded. Silicone-based transdermal patches showed higher drug release than creams which could potentially be useful for systemic hesperetin delivery for the treatment of CNS disorders, while hesperetin creams could be more suitable for the localised delivery to the skin for the treatment of skin cancers. In order to highlight non-pharmaceutical approaches to optimise CNS therapeutic outcomes, we applied pharmacokinetic modelling to examine potential dose adjustments that would be required in challenging population groups, namely pregnancy, for two antidepressants, paroxetine and sertraline. Paroxetine has been demonstrated to undergo gestation related reductions in plasma concentrations, to an extent which is dictated by the polymorphic state of CYP 2D6. However, knowledge of appropriate dose titrations is lacking. A pharmacokinetic modelling approach was applied to examine gestational changes in trough plasma concentrations for CYP 2D6 phenotypes, followed by necessary dose adjustment strategies to maintain paroxetine levels within a therapeutic range of 20-60 ng/mL. A decrease in trough plasma concentrations was simulated throughout gestation for all phenotypes. A significant number of ultra-rapid (UM) phenotype subjects possessed trough levels below 20 ng/mL (73-76 %) compared to extensive metabolisers (EM) (51-53 %). For all phenotypes studied there was a requirement for daily doses in-excess of the standard 20 mg dose throughout gestation. The following doses are suggested to be optimal: for EM, 30 mg daily in trimester 1 followed by 40 mg daily in trimesters 2 and 3, for poor-metabolisers (PM), 20 mg daily dose in trimester 1 followed by 30 mg daily in trimesters 2 and 3, and for UM, a 40 mg daily dose throughout gestation. Sertraline is also known to undergo changes in pharmacokinetics during pregnancy. CYP 2C19 has been implicated in the inter-individual variation in clinical effect associated with sertraline activity. However, knowledge of suitable dose titrations during pregnancy and within CYP 2C19 phenotypes is lacking. A pharmacokinetic modelling virtual clinical trials approach was implemented to assess gestational changes in trough plasma concentrations for CYP 2C19 phenotypes and to identify appropriate dose titration strategies to stabilise sertraline levels within a defined therapeutic range throughout gestation. Sertraline trough plasma concentrations decreased throughout gestation, with maternal volume expansion and reduction in plasma albumin being identified as possible causative reasons. All CYP 2C19 phenotypes required dose increase throughout gestation. For EM and UM phenotypes, doses of 100-150 mg daily are required throughout gestation. For PM, 50 mg daily during trimester 1 followed by a dose of 100 mg daily in trimesters 2 and 3 are required. Transdermal system is a promising approach to obtain the CNS benefits of phytochemicals and to overcome the limitations associated with their oral delivery, while more studies are needed to be used clinically. Using PBPK modelling for adjusting the doses of CNS medications in challenging populations could improve quality of life and prevent empirical interventions