Keith Gallicano

A Review of Low-Dose Ritonavir in Protease Inhibitor Combination Therapy

The pharmacokinetics of protease inhibitors center around the microsomal enzyme cytochrome P-450 3A4. As a potent inhibitor of this enzyme, ritonavir can increase the bioavailability and half-life of coadministered protease inhibitors. Evidence suggests that increased exposure to protease inhibitors is clinically relevant. Antiretroviral treatment with low-dose ritonavir-boosted lopinavir, indinavir, and saquinavir has durable virological activity and shows impressive immune reconstitution. Although tolerable in most cases, gastrointestinal side effects, hepatotoxicity, and blood lipid abnormalities remain relevant issues. Additional study will elucidate the advantages and disadvantages of twice-daily, low-dose ritonavir-boosted regimens and determine whether once-daily regimens based on this principle will have a lasting role in clinical practice.

Interaction of St John's wort with conventional drugs: systematic review of clinical trials.

Abstract Objective To determine the methodological quality of clinical trials that examined possible interactions of St Johns wort with conventional drugs, and to examine the results of these trials. Characteristics of methods used in 22 reviewed studies Name and year Study design Herb assayed Control group Blinding Randomisation Sample size discussed Mathijssen, 20025 Before and after No No No No No Markowitz, 200016 Before and after Yes No No No No Burstein, 200014 Before and after Yes No No No No Durr, 200020 Before and after No No No No No Piscitelli, 200021 Before and after Yes No No No No Mai, 20037 Before and after Yes No No No Yes Hebert, 200423 Before and after Yes No No No No Bauer, 20036 Before and after Yes No No No Yes Hall, 20038 Before and after Yes No No No Yes Jiang, 200422 Before and after Yes No No Yes Yes Johne, 20024 Before and after Yes No No No Yes Wang, 200110 Before and after Yes No No No Yes Wang, 20029 Before and after Yes No No No No Markowitz, 200324 Before and after No No No No Yes Dresser, 200325 Before and after No No No No No Roby, 200111 Before and after Yes No No No No Wenk, 200412 Before and after No No No No No Sugimoto, 200115 Crossover No Yes (placebo) Yes Yes No Pfrunder, 200317 Crossover Yes Yes No Yes No Wang, 200418 Crossover No Yes (placebo) Yes Yes No Morimoto, 200419 Crossover Yes No No No No Johne, 199913 Parallel Yes Yes (placebo) Yes No Yes Design Systematic review. Data sources Electronic databases from inception to April 2004, reference lists from published reports, and experts in the field. Study selection Eligible studies were prospective clinical trials evaluating the pharmacokinetic effect of St Johns wort on the metabolism of conventional drugs. Data extraction Two reviewers selected studies for inclusion and independently extracted data. Data synthesis 22 pharmacokinetic trials studied an average of 12 (SD 5) participants; 17 trials studied healthy volunteers and five studied patients. Most (17) studies used a “before and after” design; four studies used control groups other than the active group. Three studies randomised the sequence of administration or the participants to study arms or periods; three studies blinded participants or investigators. In 15 trials, investigators independently assayed the herb. Of 19 trials with available plasma data, three found no important interaction (change in area under the curve < 20%) and 17 found a decrease in systemic bioavailability of the conventional drug; in seven studies the 95% confidence interval excluded a decrease of < 20%. Conclusion Clinicians and patients should beware of possible decreases in the systemic bioavailability of conventional drugs when taken concomitantly with St Johns wort.

Natural health product-drug interactions: a systematic review of clinical trials.

Interactions between natural health products (NHP) and prescription medications are of increasing concern. This paper aims to identify all clinical trials of NHP-drug interactions. To determine the prevalence and outcomes of clinical investigations of NHP-drug pharmacokinetic interactions, electronic databases were searched from inception through March 2004, as well as reference lists from published reports and experts in the field for unpublished studies. Eligible studies were clinical investigations of the interaction between a NHP and the metabolism of a regulated medication in humans. Studies were excluded that only investigated the metabolism of an NHP or examined food-drug or NHP-NHP interactions. Two reviewers selected studies for inclusion and independently extracted data. Forty-seven trials were identified, studying an average of 14 participants/study (95% confidence interval [CI] 11-18), examined drug interactions with 19 different herbal preparations. All trials were pharmacokinetic studies, 41 of healthy volunteers and 6 of patients. Ten different herbal medicines as well as 5 different traditional herbal concoctions were studied. Potentially clinically significant drug interactions were observed with St. John wort (16/24 studies), garlic (2/5 studies), and American ginseng (1 study). Research on NHP-drug interactions is limited in number and scope. With the exception of St. John wort, clinicians and the public do not have information that permits strong inferences about interactions between NHPs and conventional medications.

The pharmacokinetics of nelfinavir and M8 during pregnancy and post partum

The objective of this study was to explore the pharmacokinetics of nelfinavir and its active metabolite hydroxy‐t‐butylamidenelfinavir (M8) during pregnancy and post partum.

Effect of antacids in didanosine tablet on bioavailability of isoniazid.

The antacids in two didanosine placebo tablets had no significant effect on the plasma pharmacokinetics of a single oral dose of 300 mg of isoniazid administered to 12 healthy volunteers. These results suggest that isoniazid bioavailability will be unaffected by the antacids in didanosine tablets when the two medications are administered simultaneously to human immunodeficiency virus-seropositive patients.

Antiretroviral-Drug Concentrations in Semen

In a recent minireview ([2][1]), Kashuba et al. provide physicochemical and pharmacokinetic data to rationalize how anti-HIV agents are distributed in human seminal compartments. Unfortunately, the acid-base characteristics of 9 of the 12 drugs in their Table 2 are categorized incorrectly. The

Relationship between body weight, body surface area and serum zidovudine pharmacokinetic parameters in adult, male HIV-infected patients.

ObjectiveTo determine whether there is a simple relationship between body weight or body surface area (BSA) and serum zidovudine pharmacokinetic parameters in patients receiving oral zidovudine. DesignSingle-dose, pharmacokinetic study. PatientsFifty-three asymptomatic and symptomatic HIV-infected men (CD4+ cell count < 500 × 106/l) participated in the study. Results of renal function and haematology tests were within normal limits and all hepatic function tests were up to three times the upper limit of normal. Patients received 200 mg oral zidovudine and serial blood samples were collected for 4h (18 patients) or 8 h (35 patients). Serum zidovudine concentrations were measured by high-performance liquid chromatography (12 patients) or radioimmunoassay (41 patients). Pharmacokinetic parameters were calculated by non-compartmental methods. The relationships between body weight or BSA and maximum serum concentration (Cmax), area under the concentration-time curve (AUC), apparent serum clearance (CL/F), and apparent terminal volume of distribution (VZ/F) were determined by simple least-squares linear regression. ResultsThere were no significant relationships between either body weight or BSA and Cmax, AUC, VZ/F (corrected for weight), and clearance (P > 0.07; R2 < 0.06 for all comparisons). A significant positive association between VZ/F, uncorrected for weight, and either weight (P = 0.011; R2 = 0.121) or BSA (P = 0.022; R2 = 0.098) was observed. The interindividual coefficients of variation of CL/F and VZ/F values were only marginally reduced when the parameters were corrected for weight (31.3 versus 30.8% and 28.0 versus 26.0%, respectively). ConclusionsThere is little or no linear association between either body weight or BSA and observed serum zidovudine concentrations following administration of 200 mg zidovudine in adult male patients who are within 20% of their ideal weight.

Reduced Oral Absorption of Tuberculosis Drugs in HIV Infection

Clinical Pharmacology & Therapeutics (1996) 59, 142–142; doi: 10.1038/sj.clpt.1996.66

Pharmacokinetics of simultaneously administered zidovudine and didanosine in HIV-seropositive male patients.

Our objective was to determine whether a pharmacokinetic interaction exists between zidovudine and didanosine when they are coadministered. This was designed as a randomized, three-period, three-treatment, six-sequence, crossover study with a 1-week washout period between treatments. The patients were six men infected with human immunodeficiency virus who were asymptomatic. On three separate occasions, patients received zidovudine alone (200 mg every 8 h) for 3 days, didanosine alone (200 mg every 12 h) for 3 days, or zidovudine and didanosine for 3 days. On the fourth day, each patient received the final dose of each regimen, and blood and urine were serially collected for 8 h. Pharmacokinetic parameters were assessed for zidovudine, its glucuronide metabolite (GZDV), and didanosine. Coadministration of zidovudine had no significant effect on didanosine pharmacokinetic parameters (< 12% difference between treatment means, p > 0.1). Coadministration of didanosine did not significantly alter zidovudine pharmacokinetic parameters but did cause statistically significant increases in the renal and apparent formation clearances of GZDV (18.5% and 30.5% difference between the treatment means, respectively, p < 0.025). Therapeutic doses of zidovudine did not alter didanosine pharmacokinetic parameters. Coadministration of didanosine did not affect zidovudine parameters but did cause small alterations in GZDV pharmacokinetic values. These changes are unlikely to be clinically significant.

Effect of bismuth subsalicylate on ciprofloxacin bioavailability.

A single oral dose of 528 mg of bismuth subsalicylate (30 ml of Pepto-Bismol) had no significant effect on the plasma pharmacokinetics of a single oral dose of 750 mg of ciprofloxacin administered to 12 healthy volunteers (six men and six women). These results suggest that ciprofloxacin bioavailability will not be significantly decreased by single doses of bismuth subsalicylate when the two medications are administered simultaneously.