Francesca Aweeka

University of California, San Francisco, San Francisco, California, United States

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Publications (112)542.17 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Nonnucleoside reverse transcriptase inhibitor-based antiretroviral therapy is not suitable for all treatment-naive HIV-infected persons.
    Annals of internal medicine 10/2014; 161(7):461-471. · 13.98 Impact Factor
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    ABSTRACT: We evaluated the pharmacokinetics (pk) of raltegravir in HIV-infected women during pregnancy and postpartum.
    Journal of acquired immune deficiency syndromes (1999). 08/2014;
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    ABSTRACT: Chemoprevention offers a promising strategy for prevention of malaria in African children. However, the optimal chemoprevention drug and dosing strategy is unclear in areas of year-round transmission and resistance to many antimalarial drugs. To compare three available regimens, we conducted an open-label randomized controlled trial of chemoprevention in Ugandan children.
    PLoS Medicine 08/2014; 11(8):e1001689. · 15.25 Impact Factor
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    ABSTRACT: To support the development of a dynamic in vitro human pharmacokinetic/pharmacodynamic simulation model for biofilm-mediated infections and study stability of meropenem, an LC-MS/MS method for the determination of meropenem in Luria Bertani (LB) media was developed and validated in an API2000 LC-MS/MS system. A partial validation was also performed in M9 media. Sample aliquots of 100μL (or 25μL for M9 media) were mixed with the internal standard (IS) ceftazidime and filtered. The filtrate was directly injected onto a C8 column eluted with ammonium formate (10mM, pH 4) and acetonitrile (0.1% formic acid) in a gradient mode. ESI(+) and MRM with ion pair m/z 384→68 for meropenem and m/z 547→468 for the IS were used for quantification. The calibration curve concentration range was 50 to 25,000ng/mL. The recovery was over 98%. In LB media, significant signal suppression was observed throughout the time period of detection when compared with mobile phase solvents, but the matrix effect was compensated well with the IS. In M9 media, much less signal suppression was observed. The method is simple, fast, and reliable. Using the method, stability of meropenem in LB and M9 media were tested. No significant degradation was observed for at least 8h in both LB media (37°C) and M9 media (30°C), but more than 15% degradation was observed overnight (∼20h). The method was transferred to an API5000 LC-MS/MS system using meropenem-d6 as the IS.
    Journal of chromatography. B, Analytical technologies in the biomedical and life sciences 05/2014; 961C:71-76. · 2.78 Impact Factor
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    ABSTRACT: A method for quantification of fludarabine (FDB) and clofarabine (CFB) in human plasma was developed with an API5000 LC-MS/MS system. FDB and CFB were extracted from EDTA plasma samples by protein precipitation with trichloroacetic acid. Briefly, 50μL plasma sample was mixed with 25μL internal standard (50ng/mL aqueous 2-Cl-adensosine) and 25μL 20% trichloroacetic acid, centrifuged at 25,000×g (20,000rpm) for 3min, and then transfered to an autosampler vial. The extracted sample was injected onto an Eclipse extend C18 column (2.1mm×150mm, 5μm) and eluted with 1mM NH4OH (pH 9.6) - acetonitrile in a gradient mode. Electrospray ionization in positive mode (ESI(+)) and multiple reaction monitoring (MRM) were used, and ion pairs 286/134 for FDB, 304/170 for CFB and 302/134 for the internal standard were selected for quantification. The retention times were typically 3.72min for FDB, 4.34min for the internal standard, 4.79min for CFB. Total run time was 10min per sample. Calibration range was 0.5-80ng/mL for CFB and 2-800ng/mL for FDB. The method was applied to a clinical pharmacokinetic study in pediatric patients.
    Journal of chromatography. B, Analytical technologies in the biomedical and life sciences 05/2014; 960C:194-199. · 2.78 Impact Factor
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    ABSTRACT: Artesunate plus amodiaquine is used for malaria treatment in regions with overlapping HIV endemicity. Co-administration of artesunate/amodiaquine with antiretroviral therapy (ART) may result in drug-drug interactions, but minimal data exist. This study evaluated the impact of nevirapine-based ART, containing a backbone of zidovudine and lamivudine, on the disposition of amodiaquine and its active metabolite, desethylamodiaquine (DEAQ). This was an open-label, parallel-group pharmacokinetic comparison between HIV-infected, adult subjects receiving steady-state nevirapine-based ART (n = 10) and ART-naive subjects (control group, n = 11). All subjects received a loose formulation of artesunate/amodiaquine (200/600 mg) daily for 3 days, with serial pharmacokinetic sampling over 96 h following the final dose of artesunate/amodiaquine. Amodiaquine and DEAQ were quantified using a validated HPLC method with UV detection. Pharmacokinetic parameters were determined using standard non-compartmental methods. Exposures to both amodiaquine and DEAQ were significantly lower in the nevirapine-based ART group compared with the control group (amodiaquine AUC0-24 145 versus 204 ng·h/mL, P = 0.02; DEAQ AUC0-96 14 571 versus 21 648 ng·h/mL, P < 0.01). The AUCDEAQ/AUCamodiaquine ratio was not different between groups (ART group 116 versus control group 102, P = 0.67). Subjects on nevirapine-based ART had lower exposure to both amodiaquine and DEAQ (28.9% and 32.7%, respectively). Consequently, this may negatively impact the effectiveness of artesunate/amodiaquine in HIV-infected individuals on this ART combination.
    Journal of Antimicrobial Chemotherapy 01/2014; · 5.34 Impact Factor
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    ABSTRACT: A method for quantification of fludarabine (FDB) and clofarabine (CFB) in human plasma was developed with an API5000 LC-MS/MS system. FDB and CFB were extracted from EDTA plasma samples by protein precipitation with trichloroacetic acid. Briefly, 50 μL plasma sample was mixed with 25 μL internal standard (50 ng/mL aqueous 2-Cl-adensosine) and 25 μL 20% trichloroacetic acid, centrifuged at 25,000 g (20,000 rpm) for 3 min, and then transfered to an autosampler vial. The extracted sample was injected onto an Eclipse extend C18 column (2.1 × 150 mm, 5 μm) and eluted with 1 mM NH4OH (pH 9.6) - acetonitrile in a gradient mode. Electrospray ionization in positive mode (ESI+) and multiple reaction monitoring (MRM) were used, and ion pairs 286/134 for FDB, 304/170 for CFB and 302/134 for the internal standard were selected for quantification. The retention times were typically 3.72 min for FDB, 4.34 min for the internal standard, 4.79 min for CFB. Total run time was 10 min per sample. Calibration range was 0.5-80 ng/mL for CFB and 2-800 ng/mL for FDB. The method was applied to a clinical pharmacokinetic study in pediatric patients
    Journal of Chromatography B. 01/2014;
  • 01/2014; 20(2):S30.
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    ABSTRACT: To support the development of a dynamic in vitro human pharmacokinetic/pharmacodynamic simulation model for biofilm-mediated infections and study stability of meropenem, an LC-MS/MS method for the determination of meropenem in Luria Bertani (LB) media was developed and validated in an API2000 LC-MS/MS system. A partial validation was also performed in M9 media. Sample aliquots of 100 μL (or 25 μL for M9 media) were mixed with the internal standard (IS) ceftazidime and filtered. The filtrate was directly injected onto a C8 column eluted with ammonium formate (10 mM, pH 4) and acetonitrile (0.1% formic acid) in a gradient mode. ESI+ and MRM with ion pair m/z 384→68 for meropenem and m/z 547→468 for the IS were used for quantification. The calibration curve concentration range was 50 to 25,000 ng/mL. The recovery was over 98%. In LB media, significant signal suppression was observed throughout the time period of detection when compared with mobile phase solvents, but the matrix effect was compensated well with the IS. In M9 media, much less signal suppression was observed. The method is simple, fast, and reliable. Using the method, stability of meropenem in LB and M9 media were tested. No significant degradation was observed for at least 8 h in both LB media (37 °C) and M9 media (30 °C), but more than 15% degradation was observed overnight (∼20 h). The method was transferred to an API5000 LC–MS/MS system using meropenem-d6 as the IS.
    Journal of Chromatography B. 01/2014; 961:71–76.
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    ABSTRACT: Fludarabine is a nucleoside analog routinely used in conditioning regimens of pediatric allogeneic stem cell transplantation to promote stem cell engraftment. In children, it remains a challenge to accurately and precisely quantify the active intracellular triphosphate species of fludarabine in vivo, primarily due to limitations on blood volume and inadequate assay sensitivity. Here we report a liquid chromatography tandem mass spectrometry (LC-MS/MS) method for determination of fludarabine triphosphate in human peripheral blood mononuclear cells (PBMC). PBMC (∼5 million cells) were collected and lysed in 1mL 70% methanol containing 1.2mM tris buffer (pH 7.4). The lysate (80μL) was mixed with internal standard (2-chloro-adenosine triphosphate, 150ng/mL, 20μL) and injected onto an API5000 LC-MS/MS system. Separation was achieved on a hypercarb column (100mm×2.1mm, 3μm) eluted with 100mM ammonium acetate (pH 9.8) and acetonitrile in a gradient mode at a flow rate of 0.4mL/min. Multiple reactions monitoring (MRM) and electrospray ionization in negative mode (ESI(-)) were used for detection. The ion pairs 524.0/158.6 for the drug and 540.0/158.8 for the IS were selected for quantification and 524.0/425.7 used for confirmation. Retention time was 3.0 and 3.4min for fludarabine triphosphate and the IS, respectively. The concentration range for the calibration curve was 1.52-76nM. Our method is simple, fast, and has been successfully applied in a clinical dose-concentration study in children to quantify intracellular fludarabine in low volume clinical samples. The median concentration was 1.03 and 3.19pmole/million PBMC at trough and peak time points, respectively. Fludarabine triphosphate is degraded in water within hours but relatively stable in 70% methanol-tris (1.2mM, pH 7.4). One limitation is that the hypercarb column takes a longer time to equilibrate than conventional reverse phase columns, and peaks become broad and distorted if the column is not washed and stored properly.
    Journal of pharmaceutical and biomedical analysis 08/2013; 86C:198-203. · 2.45 Impact Factor
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    ABSTRACT: Pregnancy and food insecurity may impact antiretroviral (ART) pharmacokinetics (PK), adherence and response. We sought to quantify and characterize the PK of lopinavir/ritonavir (LPV/r) and efavirenz (EFV) by pregnancy and nutritional status among HIV-infected women in Tororo, Uganda. In 2011, 62/225 ante-partum/post-partum single dried blood spot samples DBS and 43 post-partum hair samples for LPV/r were derived from 116 women, 51/194 ante-/post-partum DBS and 53 post-partum hair samples for EFV from 105 women. 80% of Ugandan participants were severely food insecure, 26% lost weight ante-partum, and median BMI post-partum was only 20.2 kg/m(2) . Rich PK-data of normally nourished (pregnant) women and healthy Ugandans established prior information. Overall, drug exposure was reduced (LPV -33%, EFV -15%, ritonavir -17%) compared to well-nourished controls [p < 0.001], attributable to decreased bioavailability. Pregnancy increased LPV/r clearance 68% [p < 0.001], whereas EFV clearance remained unchanged. Hair concentrations correlated with plasma-exposure [p < 0.001], explaining 29% PK-variability. In conclusion, pregnancy and food insecurity were associated with lower ART exposures in this cohort of predominantly underweight women, compared to well-nourished women. Much variability in plasma-exposure was quantified using hair concentrations. Addressing malnutrition as well as ART-PK in this setting should be a priority.
    The Journal of Clinical Pharmacology 08/2013; · 2.84 Impact Factor
  • Journal of acquired immune deficiency syndromes 08/2013; 63(5):578-84.
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    ABSTRACT: Background Alcohol use is common among people with HIV, and beliefs about alcohol interactions with medications predict decreased medication adherence, risking drug-resistant mutations. Maraviroc is an HIV entry inhibitor approved for treatment of both drug-sensitive and drug-resistant HIV strains. The present study evaluated the effects of alcohol on maraviroc pharmacokinetics and the effects of maraviroc on alcohol pharmacokinetics.Methods Ten healthy adults completed alcohol (1 g/kg) and placebo alcohol pharmacokinetics sessions before and after 7 days of maraviroc administration.ResultsAlcohol concentrations increased 12% following maraviroc. Maraviroc pharmacokinetics were unaffected by alcohol.Conclusions Maraviroc treatment should not be interrupted if alcohol is consumed.
    Journal of the International Association of Providers of AIDS Care. 07/2013;
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    ABSTRACT: Background: Numerous methods have been reported for the determination of artemether (ARM) and its metabolite dihydroartemisinin (DHA) in plasma. However, stability issues in patient plasma have not received enough attention. Results: An LC-MS/MS method for simultaneous determination of ARM and DHA in human plasma (K3EDTA) turned out to be problematic: ARM and DHA were degraded partially or completely in some patient plasma samples as indicated by the stable isotope-labeled internal standards. We postulated iron II (Fe(2+)) in hemoglobin or its derived products from malaria patients causes degradation of the drugs, and found that hydrogen peroxide (H2O2) protected the drugs from degradation. Acidifying plasma increased recovery of ARM significantly. Using only 50 µl of plasma sample, the method has a LLOQ at 0.5 ng/ml for both ARM and DHA. Conclusion: H2O2 is a stabilizing agent for artemisinin derivatives. The modified method is reliable and sensitive.
    Bioanalysis 06/2013; 5(12):1501-1506. · 3.25 Impact Factor
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    ABSTRACT: Background. Rifampin(RIF) upregulates CYP 450 isoenzymes potentially lowering efavirenz (EFV) exposure. The US EFV package insert recommends EFV dose increase for patients on RIF weighing ≥50&emsp14;kg. We conducted a pharmacokinetic study to evaluate EFV trough concentrations(Cmin) and HIV virologic suppression in patients on EFV(600&emsp14;mg) and RIF-based TB treatment as part of a multicenter randomized trial(ACTG A5221) Methods. EFV Cmin was measured using HPLC 20-28 hours post-EFV dose at weeks 4,8,16,24 on-RIF and weeks 4,8 off-RIF. Results evaluated with two-sided Wilcoxon rank-sum, chi-square and Fisher's Exact tests and logistic regression(5% Type I error rate). Results. 780 patients from 11 countries received EFV, 543 provided≥1 EFV Cmin. Median(IQR) weight was 52.8&emsp14;kg(48.0,59.5), BMI 19.4&emsp14;kg/m(2)(17.5,21.6), age 34(29,41), 63% male, race Black(74%), Hispanic(20%), non-Hispanic White(5%), Asian(1%). Median Cmin was 1.96&emsp14;µg/mL on-RIF vs. 1.80 off-RIF (p=0.067). EFV concentrations were significantly higher on-RIF vs. off-RIF in Blacks(2.08 vs. 1.75,p=0.005). Weight ≥60&emsp14;kg on-RIF, compared to <60&emsp14;kg, was associated with lower EFV Cmin(1.68 vs. 2.02,p=0.021). However, weight ≥60&emsp14;kg was associated with more frequent HIV RNA<400 copies/mL at week 48, compared to weight <60&emsp14;kg(81.9% vs. 73.8%,p=0.023). Conclusions. Co-administration of EFV and RIF-based TB therapy was associated with a trend toward higher, not lower, EFV Cmin compared to EFV alone, which was statistically significant in Black patients. Patients weighing ≥60&emsp14;kg had lower median EFV Cmin vs. those <60&emsp14;kg, but there was no association of higher weight with reduced virologic suppression. These data do not support weight-based dosing of EFV with RIF coadministration.
    Clinical Infectious Diseases 04/2013; · 9.37 Impact Factor
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    ABSTRACT: OBJECTIVE: African potato (Hypoxis obtusa) is commonly used in Sub-Saharan Africa as a complementary herbal remedy for HIV-infected patients. It is unknown whether or not co-administration of African potato alters the pharmacokinetics of protease inhibitor antiretrovirals. The objective of this study was to investigate the impact of the African potato on the steady-state pharmacokinetics of ritonavir-boosted lopinavir (LPV/r). METHODS: Sixteen adult volunteers were administered LPV/r 400/100mg twice a day for 14 days, followed by concomitant administration with African potato given once daily for 7 days. Lopinavir plasma exposure as estimated by the area under the concentration-time curve over the 12-h dosing interval (AUC0-12h, AUCτ) was determined on day 14 and again on day 21. Lopinavir in plasma was analyzed using a validated liquid chromatography with tandem mass spectrometry (LC-MS/MS) method. Steady-state AUCτ and the maximum concentration following dose administration (Cmax) were determined using non-compartmental methods using WinNonlin Professional version 5.2.1. Statistical analyses were performed using Stata version 12.1. RESULTS: Co-administration of African potato was not associated with any change in lopinavir AUCτ, Cmax, or Ctrough. CONCLUSIONS: African potato when taken concomitantly with LPV/r is well-tolerated and not associated with clinically significant changes in lopinavir pharmacokinetics.
    International journal of infectious diseases: IJID: official publication of the International Society for Infectious Diseases 04/2013; · 2.17 Impact Factor
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    ABSTRACT: Safe, effective concomitant treatment regimens for tuberculosis (TB) and HIV infection are urgently needed. Bedaquiline (BDQ) is a promising, new anti-TB drug and efavirenz (EFV) a commonly used antiretroviral. Due to EFV's induction of cytochrome P450 3A4, the metabolic enzyme responsible for BDQ biotransformation, the drugs are expected to interact. Based on data from a Phase I, single-dose pharmacokinetic study, a non-linear mixed effects model characterizing BDQ pharmacokinetics and interaction with multiple dose EFV was developed. BDQ pharmacokinetics were best described by a 3-compartment disposition model with absorption through a dynamic transit-compartment model. Metabolites M2 and M3 were described by 2-compartment models with clearance of BDQ and M2, respectively, as input. Impact of induction was described as an instantaneous change in clearance one week after initialization of EFV treatment, and estimated for all compounds.The model predicts average steady-state concentrations of BDQ and M2 to be reduced by 52% (RSE 3.7%) with chronic co-administration. A range of models with alternative structural assumptions regarding onset of induction effect and fraction metabolized resulted in similar estimates of the typical reduction and did not offer a markedly better fit to data.Simulations to investigate alternative regimens mitigating the estimated interaction effect were performed. The results suggest that simple adjustments of the standard regimen during EFV co-administration can prevent reduced exposure to BDQ without increasing exposures to M2. However, exposure to M3 would increase. Evaluation in clinical trials of adjusted regimens is necessary to ensure appropriate dosing for HIV-infected TB-patients on an EFV-based regimen.
    Antimicrobial Agents and Chemotherapy 04/2013; · 4.57 Impact Factor
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    ABSTRACT: Background. Despite its primary use in children, pharmacokinetic/pharmacodynamic (PK/PD) data on dihydroartemisinin-piperaquine (DP) in young children is lacking.Methods. We conducted a prospective PK/PD study of piperaquine in 107 young children in Uganda. Samples were collected up to 28 days after 218 treatments for malaria occurring over 5 months of follow-up. Malaria follow-up was conducted actively to day 28 and passively to day 63.Results. Median day-7 capillary piperaquine concentration was 41.9&emsp14;ng/mL. Low piperaquine concentrations were associated with the risk of recurrent malaria up to 42 days, primarily in those receiving trimethoprim-sulfamethoxazole (TS) prophylaxis. In children not taking TS, piperaquine concentrations were only modestly associated with the risk of recurrent malaria. However, for children on TS, associations were strong and evident for all sampling days. Day 7 concentrations ≤27.3&emsp14;ng/mL were highly predictive of the risk for recurrent malaria. Notably, of 132 cases of recurrent malaria, 119 had detectable piperaquine concentrations at the time of presentation with recurrent malaria.Conclusions. These piperaquine PK/PD data represent the first in children <2 years of age. Piperaquine exposure on day 7 correlates with risk of recurrent malaria after DP treatment in children on TS prophylaxis. Interestingly, despite strong associations, infants remain at risk for malaria even in the presence of residual levels of piperaquine.
    The Journal of Infectious Diseases 02/2013; · 5.85 Impact Factor
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    ABSTRACT: Antiretroviral therapy (ART) significantly reduced the CD8+ cell non-cytotoxic anti-HIVresponse (CNAR) in twelve HIV-1-infected subjects (p < 0.0001). In separate experiments, CD8+ cells from long term survivors (LTS) were co-cultured with HIV-infected CD4+ cells using varying concentrations of anti-HIV drugs.Theantiviral function of CD8+ cells from four of fourteen LTS was reduced with exposure to 10μM nevirapine(p< 0.05). The antiviral activity of CD8+ cells from two LTS was inhibited by 5μM zidovudine. These studies indicate that nevirapine and probably zidovudine can inhibit the anti-HIV activity of CD8+ cells and thus could influence the effectiveness of ART.
    JAIDS Journal of Acquired Immune Deficiency Syndromes 02/2013; · 4.65 Impact Factor
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    ABSTRACT: Background. Population-based human immunodeficiency virus type 1 (HIV-1) RNA levels (viral load [VL]) are proposed metrics for antiretroviral therapy (ART) program effectiveness. We estimated population-based HIV RNA levels using a fingerprick-based approach in a rural Ugandan community implementing rapid ART scale-up.Methods. A fingerprick-based HIV RNA measurement technique was validated against standard phlebotomy. This technique was deployed during a 5-day community-wide health campaign in a 6300-person community. Assessments included rapid HIV antibody testing, VL, and CD4+ T-cell count via fingerprick. We estimated population HIV RNA levels and the prevalence of undetectable RNA, assessed predictors of VL via linear regression, and mapped RNA levels within community geographic units.Results. During the community-wide health campaign, 179 of 2282 adults (7.8%) and 10 of 1826 children (0.5%) tested seropositive for HIV. Fingerprick VL was determined in 174 of 189 HIV-positive persons (92%). The mean log(VL) was 3.67 log (95% confidence interval [CI], 3.50-3.83 log copies/mL), median VL was 2720 copies/mL (interquartile range, <486-38 120 copies/mL), and arithmetic mean VL was 64 064 copies/mL. Overall, 64 of 174 of individuals had undetectable RNA (37% [95% CI, 30%-44%]), 24% had VL 486-10 000; 25% had VL 10 001-100 000; and 15% had VL>100 000 copies/mL. Among participants taking ART, 83% had undetectable VL.Conclusions. We developed and implemented a fingerprick VL testing method and provide the first report of population HIV RNA levels in Africa. In a rural Ugandan community experiencing ART scale-up, we found evidence of population-level ART effectiveness, but found a substantial population to be viremic, in need of ART, and at risk for transmission.
    Clinical Infectious Diseases 12/2012; · 9.37 Impact Factor

Publication Stats

2k Citations
542.17 Total Impact Points

Institutions

  • 1989–2014
    • University of California, San Francisco
      • • Department of Clinical Pharmacy
      • • Drug Research Unit (DRU)
      • • Division of Hospital Medicine
      San Francisco, California, United States
  • 2013
    • University of Melbourne
      • Department of Biochemistry and Molecular Biology
      Melbourne, Victoria, Australia
  • 2012
    • University of Ibadan
      • College of Medicine
      Ibadan, Oyo State, Nigeria
    • University of Alabama at Birmingham
      Birmingham, Alabama, United States
  • 2009–2012
    • CSU Mentor
      Long Beach, California, United States
  • 2011
    • University of the Pacific (California - USA)
      Stockton, California, United States
  • 2002
    • University of Cincinnati
      Cincinnati, Ohio, United States
    • University of California, Berkeley
      • Department of Nutritional Science and Toxicology
      Berkeley, California, United States
  • 2001
    • University of Washington Seattle
      • Department of Pharmacy
      Seattle, Washington, United States
  • 1996–2001
    • Northeastern University
      • School of Pharmacy
      Boston, MA, United States
  • 1999–2000
    • Tokyo University of Pharmacy and Life Science
      • School of Pharmacy
      Tokyo, Tokyo-to, Japan
  • 1997
    • University of Iowa
      • College of Pharmacy
      Iowa City, IA, United States