Artemisinin derivatives are key to the current global treatment approach for malaria. However, much remains unknown regarding the pharmacokinetics of these agents, particularly in children and pregnant women, two groups highly vulnerable to development of severe malaria infection. In this thesis, nonlinear mixed effects modeling is used to characterize the pharmacokinetics of the artemisinin derivative artesunate and its active metabolite, dihydoartemisinin (DHA), in children and in pregnant women. Chapter 1 of this thesis contains a general review of the clinical pharmacokinetic findings for artesunate and DHA following artesunate administration by the intravenous, intramuscular, oral and rectal routes. Chapter 2 presents a population pharmacokinetic model utilizing both pediatric and adult data from one Phase II and four Phase III clinical trials evaluating the combination agent pyronaridine tetraphosphate/artesunate. The focus of the modeling described in this chapter is the evaluation of the effects of body size and gender on the pharmacokinetics of artesunate and DHA in pediatric patients with uncomplicated malaria. Chapter 3 consists of a population pharmacokinetic model built utilizing plasma artesunate and DHA concentrations from 26 parasitemic second and third trimester pregnant women and 25 parasitemic non-pregnant female controls in the Democratic Republic of Congo who received 200 mg oral artesunate. The model described in Chapter 2 is a simultaneously implemented parent-metabolite model consisting of a one compartment model for artesunate, a one compartment model for DHA, and first-order artesunate absorption. Various approaches for incorporating body size on artesunate and DHA apparent clearance and volume of distribution parameters were evaluated, with a linear body surface area model and an allometric scaling model both proving satisfactory. The effect of gender was modeled on artesunate and DHA apparent clearance and volume terms. Only the effect of gender on DHA apparent clearance could be estimated with reasonable precision, with the 95% confidence interval for the effect being almost wholly contained within the predefined 0.75 to 1.25 no relevant clinical effect interval. The model described in Chapter 3 consists of a one compartment model for artesunate, a one compartment model for DHA, and mixed zero-order, lagged first order absorption of artesunate. In this model, pregnancy was found to have a marked effect on DHA apparent clearance, with a pregnancy-associated increase in DHA apparent clearance of 42.3%. The models described in this thesis indicate that, for a given mg/kg dose of artesunate, both young children and pregnant women would be expected, on average, to display lower DHA concentrations than would be observed following administration of the same mg/kg dose to non-pregnant adults. Suboptimal dosing has clinical implications for the individual as well as potential implications regarding parasite susceptibility. Given this, the findings of the research described in this thesis highlight the necessity of investigations designed to comprehensively characterize the pharmacokinetics of artesunate and DHA in these two highly susceptible populations.

Background and Objectives: Integrase strand transfer inhibitors (INSTIs), dolutegravir, elvitegravir, and raltegravir, have become integral in the treatment of HIV, with close monitoring of continued efficacy and tolerability. As side effect occurrence varies among subjects receiving these drugs, we sought to perform an exploratory analysis examining the role of several single-nucleotide polymorphisms (SNPs) on drug concentration changes, selected clinical outcomes, and the occurrence of subject-reported adverse events. Methods: Adults (aged ≥ 18 years) receiving INSTI-based regimens for treatment of HIV were recruited and genotyped with an iPLEX ADME PGx Pro v1.0 Panel. Multiple linear or logistic regression with covariates [age, sex, BMI, regimen (in the across-regimen group), regimen duration, and baseline variables (for continuous parameters)] was used to detect significant association of selected clinical data with genetic variants within the study population. Results: In a sample with a median age of 52.5 years (IQR 45.7–57.2) being predominately Caucasian (88.6%) and male (86.4%), this exploratory study discovered several associations between variables and SNPs, when using INSTIs. Abnormal dream occurrence was statistically different between regimens. Additionally, several SNPs were found to be associated with adverse event profiles primarily when all regimens were grouped together. Conclusions: The associations found in this study point to a need for further assessment, within the population living with HIV, of factors contributing to unfavorable subject outcomes. These exploratory findings require confirmation in larger studies, which then may investigate pharmacogenetic mechanisms.

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Purpose: Three different generic vancomycin products were compared using liquid chromatography–mass spectrometry (LC-MS) and open-access metabolomic tools. Methods: Single-lot samples of vancomycin hydrochloride from three different manufacturers (Hospira, APP Pharmaceuticals, and Pfizer) were reconstituted and injected into a high-resolution LC-MS system. The mass spectral fingerprints were compared for similarity of nonvancomycin B components using the XCMS Online system through Scripps University. Significance was defined as a p of ≤0.01 and a fold change of ≥1.5. The concentration of vancomycin B in each product was also measured using LC-MS on days 0, 1, 2, 4, 7, 10, and 14. Results: Qualitative comparisons of the products using the XCMS Online interface indicated the presence of significant differences among the products at the time of reconstitution; however, these variations seemed to converge after 14 days of storage. The concentration profiles of vancomycin B during refrigerated storage did not differ significantly among the three products. XCMS Online analyses revealed that the Pfizer and Hospira products were the most similar to each other. Conclusion:While there were no significant differences found in the concentration of vancomycin B among Pfizer, APP, and Hospira products, there were differences in their initial mass spectral analysis after reconstitution. Liquid chromatography–tandem mass spectrometry profiles of the ions or isotopes present in the three products showed significant differences in impurities such as crystalline degradation product (CDP)-1 and CDP intermediate. After 14 days of refrigerated storage, the differences among the products converged, and fewer distinct features could be detected.

No description available.

No description available.

The purpose of this study was to quantify the amounts of the d- and l-threo enantiomers of methylphenidate in maternal plasma, placenta, and maternal and fetal brain tissue following prenatal exposure and to establish a pharmacokinetic profile for MPH during pregnancy. Due to increasing rates of use of methylphenidate amongst females of childbearing age, it is important to understand the extent of exposure to the fetus. Briefly, pregnant mice were injected with 5 mg/kg methylphenidate at 18 days gestation, and tissue was collected 1, 5, 10, 30, 60, and 120 min following injection. Methylphenidate was extracted from tissue via solid phase extraction, and concentrations were determined using liquid chromatography–mass spectrometry (LC–MS). Because methylphenidate is administered as a racemic mixture of d- and l-threo enantiomers and the d-enantiomer is more pharmacologically active, the enantiomers were quantified separately. Interestingly, we found that methylphenidate does cross the placenta and enter the fetal brain. Although the highest concentrations were achieved in maternal brain, the concentrations of d- and l-methylphenidate in fetal brain were comparable to those of maternal plasma. Additionally, both d- and l-methylphenidate had longer half-lives in placenta than in maternal or fetal brain. Interestingly, there was a bimodal peak in maternal brain concentrations, at 5 min and again at 60 min, which was not observed in maternal plasma. Finally, the total exposure (as represented by area under the curve) was statistically significantly higher for the active d-enantiomer than the l-enantiomer in maternal brain tissue. In conclusion, methylphenidate crosses the placenta and reaches measurable concentrations in fetal brain. Although long-term behavioral and developmental studies are needed to determine specific outcomes of prenatal exposure, discussion with pregnant patients on the potential risks of methylphenidate exposure is warranted.

No description available.

No description available.

The abuse of synthetic cathinones, formerly marketed as “bath salts”, has emerged over the last decade. Three common drugs in this class include 3,4-methylenedioxypyrovalerone (MDPV), 4-methylmethcathinone (mephedrone), and 3,4-methylenedioxymethcathinone (methylone). An LC–MS/MS method has been developed and validated for the simultaneous quantification of MDPV, mephedrone, and methylone in brain tissue. Briefly, MDPV, mephedrone, methylone, and their deuterium-labeled analogs were subjected to solid phase extraction (SPE) and separated using an HILIC Silica Column. The HPLC was coupled to a Shimadzu IT-TOF (ion trap-time of flight) system with the electrospray source running in positive mode (+ESI). The method was validated for precision, accuracy, and extraction efficiency. All inter-day and intra-day % RSD (percent relative standard deviation) and % error values were less than 15% and extraction efficiency exceeded 80%. These conditions allowed for limits of detection of 1ng/mL for MDPV, and 5 ng/mL for both mephedrone and methylone. The limits of quantification were determined to be 5ng/mL for MDPV and 10 ng/mL for mephedrone and methylone. The method was utilized to evaluate the pharmacokinetics of these drugs in adult male rats following administration of a drug cocktail including MDPV, mephedrone, and methylone. All three compounds reached peak concentrations in the brain within 15 min. Although methylone and mephedrone were administered at the same dose, the peak concentration (Cmax) of mephedrone in the brain was significantly higher than that for methylone, as was the area under the curve (AUC). In summary, this quick and sensitive method for measuring synthetic cathinones may be used for future pharmacokinetic investigations of these drugs in target tissue.