Ronald C Reed

Abbott Laboratories, North Chicago, IL, United States

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Publications (13)28.74 Total impact

  • Ronald Charles Reed, Sandeep Dutta, Wei Liu
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    ABSTRACT: Divalproex sodium extended-release (divalproex-ER), administered once-daily, maintains plasma valproic acid (VPA) concentrations for 24h, whereas enteric-coated, delayed-release divalproex sodium (divalproex) requires multiple-daily doses to do the same. We hypothesize that a once-daily divalproex regimen should not be administered to epilepsy patients requiring high total daily doses, e.g., 35.6-56 mg/kg/day, due to the potential for high (>125 mg/L) maximum VPA concentrations (C(max)). We examined the impact of once-daily dosing, divalproex vs. divalproex-ER, on steady-state plasma VPA concentration-time profiles at commonly used doses in monotherapy (uninduced) and polytherapy (hepatic enzyme-induced) virtual adult patients. Only the 1125 mg once-daily divalproex dose had mean C(max)<100mg/L; >or=2000 mg produced mean C(max)>or=125 mg/L. Mean divalproex C(min) was approximately 50 mg/L at two of four doses tested, whereas mean ER C(min) was >73 mg/L at all doses tested. Once-daily divalproex peak-trough fluctuation was 4.4-6.2-fold greater than once-daily divalproex-ER. We predict that excursions beyond the conventional recommended VPA plasma concentration range will commonly occur with high total mg daily doses (>or=2000 mg) of enteric-coated divalproex, if dosed once-daily, potentially producing clinical toxicity. This divalproex formulation should not be dosed once-daily at high total mg daily doses due to this risk. Divalproex-ER is the appropriate formulation for administration on a once-daily basis, especially if large total mg/day doses are required for the control of seizure activity.
    Epilepsy research 11/2009; 87(2-3):260-7. · 2.48 Impact Factor
  • Sandeep Dutta, Ronald C Reed
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    ABSTRACT: Five oral formulations of valproic acid (VPA)/divalproex sodium are approved and commonly used in the US for treatment of epilepsy, mania/bipolar disorder and migraine prophylaxis. These formulations have unique pharmacokinetic and formulation characteristics and are designed to treat distinct patient populations. We compared the absorption characteristics of all five oral VPA/divalproex formulations currently available in the US. Plasma VPA concentration-time profiles, following single oral dose (250mg) administration of five VPA/divalproex formulations under fasting conditions, from three pharmacokinetic studies in healthy subjects (N=9-15 each) were compared. The five VPA/divalproex formulations demonstrated marked absorption differences. The rate of absorption, as characterized by maximum concentration (C(max)) and time to C(max) (T(max)), may be rank-ordered as: VPA syrup (34.2mg/L, 0.9h)>VPA capsule (31.4mg/L, 2.2h)>divalproex sodium sprinkle capsule (20.7mg/L, 4.0h; lag-time congruent with1h) congruent withdivalproex sodium enteric-coated delayed-release tablet (26.0mg/L, 3.4h; lag-time congruent with2h)>divalproex sodium extended-release (divalproex-ER) tablet (11.8mg/L, 19.7h). Divalproex-ER had approximately 11% lower exposure (AUC). The comparable AUC across the five formulations, when corrected for bioavailability differences, demonstrates that formulation primarily affects the drug-release and in vivo absorption of VPA. Only divalproex-ER demonstrated true sustained-release characteristics.
    Epilepsy Research 04/2007; 73(3):275-83. · 2.24 Impact Factor
  • Sandeep Dutta, Ronald C Reed
    The Journal of Clinical Pharmacology 09/2006; 46(8):952-7. · 2.84 Impact Factor
  • Ronald C Reed, Sandeep Dutta
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    ABSTRACT: Divalproex sodium extended-release (divalproex-ER) is a novel formulation intended for once-daily oral administration, either morning or evening. Questions have risen concerning the optimal time for obtaining a blood sample for valproic acid (VPA) concentration in relation to the dose. Trough sampling is easily achieved just before a morning daily dose, but the best time to sample after an evening daily dose is unclear, because collecting a blood sample 21 to 24 hours later may be limited by the operational hours of the laboratory. This investigation provides practical guidance regarding blood sample timing. Steady-state plasma VPA concentration-time profiles from 5 published divalproex-ER studies (healthy subjects and epilepsy patients) were analyzed. The concentration-time profile for each subject/patient was expressed as a percentage of his/her trough concentration and summary statistics computed. Typically, when taking divalproex-ER once daily in the morning, a blood sample collected 21 to 24 hours later is expected to have a concentration within 3% of the trough value. Conversely, for divalproex-ER dosed once-daily in the evening, for example 8 PM, a blood draw 12 to 15 hours later (ie, 8 to 11 AM) will give a plasma VPA concentration value that is 18% to 25% higher, on average, than the trough value. However, waiting longer, (for example 18 to 21 hours, ie 2 to 5 PM) will result in concentration values that are merely 3% to 13% higher than trough values, which may provide acceptable information for monitoring purposes. The greatest deviation from trough VPA concentration occurs around the peak, that is 3 to 15 hours after a once-daily divalproex-ER dose; sampling during this time period is recommended only if a clinical need exists to test for a higher VPA concentration. Despite the apparent smoothness of the VPA concentration-time profile after a once-daily divalproex-ER dose, the timing of the blood sample does matter and impacts the proper interpretation of the VPA concentration.
    Therapeutic Drug Monitoring 07/2006; 28(3):413-8. · 2.23 Impact Factor
  • Sandeep Dutta, Ronald C Reed
    American Journal of Health-System Pharmacy 06/2006; 63(10):904-6. · 1.98 Impact Factor
  • Source
    Sandeep Dutta, Ronald C Reed, Robert F O'Dea
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    ABSTRACT: The distinct absorption characteristics of the conventional enteric-coated, delayed-release (DR) and the novel extended-release (ER) divalproex sodium formulations are not well recognized. To quantitatively and qualitatively differentiate the absorption characteristics of divalproex-DR and -ER formulations. Healthy volunteers (N = 28) received single 1000 mg doses of divalproex-DR and divalproex-ER tablets in a crossover fashion. Noncompartmental and compartmental analyses were used to estimate valproic acid (VPA) pharmacokinetics from the plasma concentration-time profiles determined from intensive blood sampling over 48 hours. VPA was not absorbed from divalproex-DR in the first 2 hours (absorption lag-time) after dosing. After VPA release in the intestine, approximately 63% of the dose was absorbed in less than 1 hour, that is, 2.9 hours (mean absorption time) from dosing. Maximum concentration (C(max)) was achieved approximately 4 hours after dosing. VPA absorption was complete ( approximately 93% of dose) within 3 absorption half-lives ( approximately 4.5 h) post-absorption lag-time, that is, 6-7 hours from dosing. In contrast, VPA absorption from divalproex-ER starts immediately after administration, initially at a modest rate, followed by slow and extended absorption at a constant rate for more than 20 hours; VPA concentrations at 1 and 2 hours were 28% and 40% of C(max). Approximately 53% of the dose was absorbed within 12 hours (mean absorption time); complete absorption occurred over more than 20 hours without any dose dumping. VPA absorption from enteric-coated divalproex-DR is rapid following a lag-time of approximately 2 hours and is complete within 6-7 hours of dosing. In contrast, VPA absorption from divalproex-ER starts immediately after administration, but occurs at a slow, approximately constant rate over more than 20 hours.
    Annals of Pharmacotherapy 05/2006; 40(4):619-25. · 2.57 Impact Factor
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    ABSTRACT: Extended-release divalproex sodium (divalproex-ER) biopharmaceutics after every-12-hour (q12h) administration was compared with that of once-daily divalproex-ER and conventional divalproex given every 6 hours (q6h) in a multiple-dose (14-day), randomized, three-period crossover design study in 24 patients with epilepsy concomitantly receiving enzyme-inducing antiepileptic medication(s). Plasma valproic acid (VPA) minimum concentration (Cmin) for divalproex-ER q12h was higher than the once-daily divalproex-ER Cmin (P=0.043). Once-daily divalproex-ER Cmin values were not different from those for divalproex q6h, suggesting that adequate trough steady-state concentrations are maintained with once daily dosing, despite enzyme-inducing comedication. The degree of peak-trough fluctuation (DFL, calculated as (Cmax-Cmin)/Cavg) in VPA concentration was less with both q12h (35.2% less) and once-daily (16.9% less) divalproex-ER regimens compared with q6h divalproex (P0.024). The DFL for divalproex-ER dosed as a q12h regimen was 22% less than that for once-daily divalproex-ER (P=0.02). The DFL in VPA concentration with divalproex-ER can be minimized with once-daily administration and more so with q12h administration, compared with conventional enteric-coated divalproex taken q6h.
    Epilepsy & Behavior 04/2006; 8(2):391-6. · 1.84 Impact Factor
  • Sandeep Dutta, Ronald C Reed
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    ABSTRACT: For many drugs, steady-state concentration-time profiles are often not optimally characterised by the intrinsic terminal elimination half-life for various reasons, including multiexponential disposition with minimal contribution of the terminal phase to steady-state exposure or use of controlled-release formulations with extended zero- or mixed zero-/first-order absorption. In such cases, 'effective' or 'functional' half-life (t((1/2)F)) has often been used to characterise steady-state pharmacokinetics. Valproic acid, commonly used in neuropsychiatry, has an elimination half-life of 4-16 hours in different populations (children vs adults, enzyme-induced vs uninduced). Divalproex-ER, a once-daily extended- release divalproex sodium formulation, is designed to release valproic acid over >18 hours. Hence the steady-state divalproex-ER concentration-time profiles have small peak-trough fluctuations that are not optimally characterised by valproic acid elimination half-life. In this study, the value of t((1/2)F) was calculated to characterise divalproex-ER steady-state concentration-time profiles. The value of t((1/2)F), defined as the time taken for the concentration to drop by one-half during a dosing interval (tau) at steady state, was derived using steady-state maximum (C(max)) and minimum (C(min)) plasma concentration and tau values, and calculated as ln(2)/(ln [C(max)/C(min)]/tau). The t((1/2)F) values of valproic acid in adult hepatic enzyme-uninduced healthy subjects and enzyme-induced epilepsy patients were calculated from five pharmacokinetic studies in which divalproex-ER was administered once daily for 6-14 days. The estimated geometric mean t((1/2)F) in uninduced adults was 40.0 hours versus the expected elimination half-life of 12-16 hours in this population (including patients on valproic acid monotherapy); for induced patients, t((1/2)F) was 26.9 hours versus the expected elimination half-life of 6-12 hours. The t((1/2)F) of valproic acid optimally characterises the expected steady-state C(max) to C(min )decrease of 33% in uninduced and 45% in induced adults following once-daily administration of divalproex-ER.
    Clinical Drug Investigation 01/2006; 26(12):681-90. · 1.92 Impact Factor
  • Ronald C Reed, Sandeep Dutta
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    ABSTRACT: Computer simulations were used to analyze changes in steady-state total plasma valproic acid concentrations when a patient misses a dose of once-daily extended-release divalproex sodium, replaces it at a later time, and resumes scheduled therapy. Valproic acid concentration-time profiles were simulated for 1000 hypothetical patients for each of two missed-dose scenarios using a one-compartment (assumes rapid distribution) population kinetic model with nonlinear protein binding. For each scenario, a lognormal distribution of clearance of unbound valproic acid, volume of distribution of unbound valproic acid, protein-binding values, and albumin concentration was generated. All simulations incorporated 20% interpatient variability and 10% residual error. Our pharmacokinetic simulations predicted that the chance for high plasma valproic acid concentrations resulting in clinical toxicity is low when extended-release divalproex doses are replaced within 12 hours followed by resumption of scheduled administration, perhaps due to the controlled, near zero-order absorption characteristics of the extended-release formulation. If a patient misses a dose of extended-release divalproex, it should be replaced as soon as the patient remembers. The next dose should be taken at the regularly scheduled time. A missed dose of extended-release divalproex may be replaced up to 12 hours later without any clinically significant change in plasma valproic acid concentrations in a majority of the patients. Simulation of two scenarios suggested that a missed dose of extended-release divalproex sodium may be replaced up to 12 hours later without any clinically significant perturbation in plasma valproic acid concentrations in the majority of adolescent and adult patients with epilepsy.
    American Journal of Health-System Pharmacy 12/2004; 61(21):2284-9. · 1.98 Impact Factor
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    ABSTRACT: The pharmacokinetics and safety of 1000-mg extended-release divalproex sodium given once daily either in the morning or evening were compared. Healthy volunteers 19-55 years of age were enrolled in this open-label, parallel-design study. Subjects were randomized to receive extended-release divalproex either in the morning or in the evening. Blood samples were taken immediately before and at 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 121, 122, 123, 124.5, 126, 127.5, 129, 130.5, 132, 133, 134, 135, 136.5, 138, 139.5, 141, 142.5, and 144 hours after the first dose of each six-day regimen. Plasma samples were assayed for total valproic acid concentrations using gas chromatography. Valproic acid pharmacokinetic values were measured, and the safety of each regimen was evaluated. Mean steady-state valproic acid exposure, maximum concentration, and minimum concentration were 1771 mg x hr/L, 86.9 mg/L, and 55.5 mg/L for the morning dosing and 1728 mg x hr/L, 84.8 mg/L, and 57.4 mg/L for the evening dosing regimens, respectively. Adverse events reported by two or more subjects were abdominal pain and somnolence for the morning dosing regimen and asthenia, headache, and pain for the evening dosing regimen. All adverse events were mild or moderate; none caused subject withdrawal from the study. There were no significant differences in the pharmacokinetic parameters (p > 0.51) and safety between groups. Diurnal variation in plasma valproic acid concentrations was minimal with once-daily administration of extended-release divalproex. Evening once-daily administration of extended-release divalproex was not associated with substantial differences in pharmacokinetics or safety compared with morning once-daily administration.
    American Journal of Health-System Pharmacy 11/2004; 61(21):2280-3. · 1.98 Impact Factor
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    ABSTRACT: Conventional delayed-release, enteric-coated divalproex sodium tablet has an absolute bioavailability of approximately 100%. Divalproex sodium extended-release (ER) tablet is a novel formulation of valproic acid (VPA) designed to release the drug slowly at a constant zero-order rate. The purpose of this study was to evaluate the absolute bioavailability and absorption characteristics of divalproex ER. Healthy adult volunteers (n = 16) received divalproex ER and intravenous VPA in crossover fashion. Absolute bioavailability was calculated as the divalproex ER/intravenous VPA ratio of area under the curve extrapolated to infinity. The duration and rate of absorption of VPA from divalproex ER tablets were determined by deconvolution analysis. The geometric mean absolute bioavailability of divalproex ER was 0.896. The mean (coefficient of variation) duration of drug absorption from divalproex ER was 21.8 (17%) hours, and the zero-order absorption rate was 21.6 (24%) mg/h for a 500-mg tablet. Divalproex ER has a lower absolute bioavailability than conventional divalproex tablets but exhibits good extended-release characteristics without any dose dumping.
    The Journal of Clinical Pharmacology 08/2004; 44(7):737-42. · 2.84 Impact Factor
  • Ronald C Reed, Sandeep Dutta
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    ABSTRACT: To examine if, during conversion from conventional divalproex to once-daily divalproex extended-release (ER) tablets, plasma valproic acid (VPA) concentrations in the first 48 hours after conversion are maintained within the accepted therapeutic range (50-100 mg/L). Four distinct 12-hourly (q12h) divalproex to once-daily divalproex ER conversion strategies were explored: immediate, delayed, stepwise and mixed conversion. These strategies were each used in simulations for hypothetical adult patients being treated under different conditions: monotherapy (uninduced, at 1500 mg/day divalproex ER) and polytherapy on enzyme-inducing co-medications (induced, at 3000 and 4500 mg/day divalproex ER). The proportion of uninduced patients expected to have minimum VPA concentrations (C(min)) >50 mg/L was 90% for immediate, 83% for stepwise and 82% for mixed-conversion strategies; only 52% undergoing a delayed-conversion strategy had C(min) >50 mg/L. More importantly, 33% of induced patients under-going delayed conversion to 3000 mg/day divalproex ER maintained an adequate VPA C(min). Maximum VPA concentrations (C(max)) attained after conversion to divalproex ER are unlikely to rise beyond the steady-state C(max) observed with divalproex q12h regimens with any conversion strategy tested in uninduced or induced patients. Marked perturbation in VPA concentration is not likely when converting to once-daily divalproex ER 'all-at-once' 12 hours after the last divalproex q12h dose. Stepwise and mixed-conversion strategies do not offer any advantage; delayed conversion may produce a large drop in VPA concentration. An ideal conversion strategy for q12h divalproex to once-daily divalproex ER appears to be an immediate conversion 12 hours after the last divalproex q12h dose; it causes the least perturbation in plasma VPA, even for patients required to take high divalproex ER doses.
    Clinical Drug Investigation 02/2004; 24(9):509-21. · 1.92 Impact Factor
  • Sandeep Dutta, Ronald C Reed
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    ABSTRACT: Divalproex extended release (ER) tablets have lower bioavailability than conventional divalproex tablets. Objectives were to provide dose-increment justification for conversion of a patient from conventional enteric-coated divalproex to a once-daily divalproex ER regimen and to discuss the pharmacokinetic factors affecting these unequal total daily dose conversions. Three bioavailability studies (two in healthy volunteers and one in epilepsy patients; total n = 69) compared equal total daily doses, and two studies (one each in healthy volunteers and epilepsy patients; total n = 99) compared 8-20% higher divalproex ER daily doses with corresponding divalproex total daily doses. In all five studies, multiple doses were administered over 6-14 days in each regimen. For equal total daily dose comparisons, the divalproex ER/divalproex bioavailability (area under the concentration-time curve [AUC] ratio) was ~0.89 and when the divalproex ER dose was higher, the two regimens were equivalent (AUC ratio ~1.0). Divalproex ER administered once daily had less fluctuation in valproic acid concentrations, i.e. divalproex ER achieved equal or significantly higher minimum concentrations and significantly lower maximum concentrations compared with divalproex administered multiple times daily. Divalproex ER predose trough concentration consistently represented the lowest concentration during a dosing interval, whereas for divalproex this was not true because of absorption lag time (from enteric coating), diurnal variation and multiple doses during a 24-hour interval. An 8-20% higher divalproex ER daily dose should be used when converting from a total daily dose of divalproex. The lower fluctuation of valproic acid concentrations, consistent time to trough concentration, and lower dosing frequency of divalproex ER should offer benefit to the patient by providing convenient once-daily administration, and to the clinician by facilitating easier and reliable therapeutic drug monitoring and improving patient adherence.
    Clinical Drug Investigation 02/2004; 24(9):495-508. · 1.92 Impact Factor

Publication Stats

73 Citations
7 Downloads
596 Views
28.74 Total Impact Points

Institutions

  • 2006–2009
    • Abbott Laboratories
      • • Global Pharmaceutical Research and Development
      • • Abbott Laboratories
      North Chicago, IL, United States