Susan M. Abdel-Rahman

Voriconazole: A New Triazole Antifungal

OBJECTIVE: To review the currently available information on the pharmacology, pharmacokinetics, efficacy, adverse effects, drug interactions, and dosage guidelines of voriconazole. Comparative data for voriconazole and other azole antifungal agents are described where available. DATA SOURCES: A MEDLINE search restricted to English-language articles (1966 to September 1999) was conducted, and an extensive review of journals and meeting abstracts was performed. MeSH headings included itraconazole, fluconazole, voriconazole, UK-109,496, and amphotericin B. DATA EXTRACTION: The data on pharmacokinetics, adverse effects, and drug interactions were obtained from open-label and controlled studies and case reports. Controlled studies and case reports were evaluated to demonstrate the efficacy of voriconazole in treatment of various fungal infections. DATA SYNTHESIS: Voriconazole is a derivative of fluconazole that demonstrates enhanced in vitro activity against existent and emerging fungal pathogens. Limited data have revealed a favorable pharmacokinetic and safety profile for the agent. Moreover, select clinical trials and case studies of voriconazole suggest good in vivo efficacy against several fungal pathogens including Candida, Aspergillus, and Scedosporium. CONCLUSIONS: Voriconazole has shown promise in the treatment of superficial and systemic mycoses. While several unresolved issues remain, voriconazole may be a viable therapeutic alternative for fluconazole-resistant mucocutaneous candidiasis and in cases of mild to moderate systemic mycoses requiring chronic treatment or that are refractory to currently available agents.

Pharmacokinetics and metabolism of intravenous midazolam in preterm infants.

Midazolam, a benzodiazepine, is finding expanded use in neonatal intensive care units. We studied the pharmacokinetics and metabolism of midazolam after a single intravenous dose in preterm infants.

Identification and characterization of novel sequence variations in the cytochrome P4502D6 (CYP2D6) gene in African Americans.

Cytochrome P4502D6 (CYP2D6) genotyping reliably predicts poor metabolizer phenotype in Caucasians, but is less accurate in African Americans. To evaluate discordance we have observed in phenotype to genotype correlation studies, select African American subjects were chosen for complete resequencing of the CYP2D6 gene including 4.2 kb of the CYP2D7-2D6 intergenic region. Comparisons were made to a CYP2D6*1 reference sequence revealing novel SNPs in the upstream, coding and intervening sequences. These sequence variations, defining four functional alleles (CYP2D6*41B, *45A and B and *46), were characterized for their ability to influence splice site strength, transcription level or catalytic protein activity. Furthermore, their frequency was determined in a population of 251 African Americans. A −692TGTG deletion (CYP2D6*45B) did not significantly decrease gene expression, nor could any other upstream SNP explain a genotype-discordant case. CYP2D6*45 and *46 have a combined frequency of 4% and can be identified by a common SNP. Carriers are predicted to exhibit an extensive or intermediate CYP2D6 phenotype.Cytochrome P4502D6 (CYP2D6) genotyping reliably predicts poor metabolizer phenotype in Caucasians, but is less accurate in African Americans. To evaluate discordance we have observed in phenotype to genotype correlation studies, select African American subjects were chosen for complete resequencing of the CYP2D6 gene including 4.2 kb of the CYP2D7-2D6 intergenic region. Comparisons were made to a CYP2D6*1 reference sequence revealing novel SNPs in the upstream, coding and intervening sequences. These sequence variations, defining four functional alleles (CYP2D6*41B, *45A and B and *46), were characterized for their ability to influence splice site strength, transcription level or catalytic protein activity. Furthermore, their frequency was determined in a population of 251 African Americans. A −692TGTG deletion (CYP2D6*45B) did not significantly decrease gene expression, nor could any other upstream SNP explain a genotype-discordant case. CYP2D6*45 and *46 have a combined frequency of 4% and can be identified by a common SNP. Carriers are predicted to exhibit an extensive or intermediate CYP2D6 phenotype.

Single dose pharmacokinetics of linezolid in infants and children.

Background. Linezolid is an oxazolidinone antibiotic with excellent in vitro activity against a number of Gram-positive organisms including antibiotic-resistant isolates. The safety and pharmacokinetics of intravenously administered linezolid were evaluated in children and adolescents to examine the potential for developmental dependence on its disposition characteristics. Methods. Fifty-eight children (3 months to 16 years old) participated in this study; 44 received a single 1.5-mg/kg dose and 14 received a single 10-mg/kg dose of linezolid administered by intravenous infusion. Repeated blood samples (n = 10 in children ≥12 months;n = 8 in children 3 to 12 months) were obtained during 24 h after drug administration, and linezolid was quantitated from plasma by high performance liquid chromatography with mass spectrometry detection. Plasma concentration vs. time data were evaluated with a model independent approach. Results. Linezolid was well-tolerated by all subjects. The disposition of linezolid appears to be age-dependent. A significant although weak correlation between age and total body clearance was observed. The mean (±sd) values for elimination half-life, total clearance and apparent volume of distribution were 3.0 ± 1.1 h, 0.34 ± 0.15 liter/h/kg and 0.73 ± 0.18 liter/kg, respectively. Estimates of total body clearance and volume of distribution were significantly greater in children than historical values of adult data. As such maximum achievable linezolid plasma concentrations were slightly lower in children, and concentrations 12 h after a single 10-mg/kg dose were below the MIC90 for selected pathogens with in vitro susceptibility to the drug. Conclusion. Based on these data a linezolid dose of 10 mg/kg given two to three times daily would appear appropriate for use in pediatric therapeutic clinical trials of this agent.

Investigation of terbinafine as a CYP2D6 inhibitor in vivo

Terbinafine is an orally active antifungal used in the treatment of dermatophytoses. To date, studies evaluating the effect of terbinafine on the cytochromes P450 have failed to show any significant interactions. This prospective open‐label study was designed to confirm our previous finding that terbinafine may inhibit CYP2D6.

Clinical Efficacy and Pharmacokinetics of Montelukast in Dyspeptic Children with Duodenal Eosinophilia

Background Montelukast, a competitive cysteinyl leucotriene-1 receptor antagonist, reduces airway eosinophilia in asthmatics. We evaluated the effect of this drug in children with eosinophilic duodenitis, defined histologically as duodenal mucosa with peak eosinophil count of more than 10 eosinophils/hpf. Methods Forty children and adolescents (6–18 yr) with dyspepsia and duodenal eosinophilia were enrolled in a double blind, randomized, placebo-controlled, cross-over study of monteleukast therapy. Subjects were randomized to receive either 10 mg montelukast or an identical placebo once daily and were evaluated on day 14 for symptomatic and biochemical responses. Subjects were also randomized to one of two blood sampling schemes to evaluate montelukast pharmacokinetics. Results Using a post treatment global pain assessment, a positive clinical response was observed in 62.1% of patients receiving montelukast compared with 32.4% on placebo (p < 0.02). Pain assessment score deteriorated in 45% of montelukast responders (5/11) after cross-over to placebo and improved in 62% (8/13) of placebo non-responders on cross-over to montelukast. In patients with peak duodenal eosinophil counts between 20–29/hpf (n=19), a positive pain assessment response was observed in 84% of patients receiving montelukast compared to 42% receiving placebo (p < 0.01). Response rate did not differ by age, gender or histologic findings at baseline. Pharmacokinetic analysis yielded parameter estimates for absorption rate constant (Ka), apparent volume of distribution (Vd/F) and elimination rate constant (Kel) of 0.42 h−1, 0.19 L/kg and 0.26 h−1, respectively. The relative extent of systemic drug exposure was comparable to that observed in previous pediatric investigations with similar weight-adjusted montelukast doses. Neither dose nor calculated drug exposure were associated with the level of post treatment pain assessment or the change in biochemical markers. Conclusions These data suggest a beneficial role for montelukast in the treatment of pediatric patients with dyspepsia associated with duodenal eosinophilia.

Oral Terbinafine: A New Antifungal Agent:

Objective To review the pharmacology, pharmacokinetics, efficacy, adverse effects, drug interactions, and dosage guidelines of terbinafine. Available comparative data of terbinafine and other antimycotic agents are described for understanding the potential role of terbinafine in patient care. Data Sources A MEDLINE search restricted to English language during 1966–1996 and extensive review of journals was conducted to prepare this article. MeSH headings included allylamines, terbinafine, SF 86–327, dermatophytosis, dermatomycosis. Data Extraction The data on pharmacokinetics, adverse effects, and drug interactions were obtained from open-label and controlled studies and case reports. Controlled single- or double-blind studies were evaluated to describe the efficacy of terbinafine in the treatment of various fungal infections. Data Synthesis Terbinafine is the first oral antimycotic in the allylamines class: a fungicidal agent that inhibits ergosterol synthesis at the stage of squalene epoxidation. Terbinafine demonstrates excellent in vitro activity against the majority of dermatophyte species including Trichophyton rubrum, Trichophyton mentagrophytes, and Epidermophyton floccosum; less activity is seen against Dematiaceae and the filamentous fungi. It is least active against the pathogenic yeast and this correlates with the relatively poor efficacy against these organisms in vivo. High concentrations of terbinafine are achieved in keratinous tissues, the site of superficial infections, and these concentrations are maintained for up to 3 months. The clinical efficacy of terbinafine against a number of dermatophyte infections exceeds that of the current standard of therapy, griseofulvin. The efficacy of terbinafine may be as good or better than that of the azole antifungals. Additional studies are required to confirm these observations. Terbinafine demonstrates a good safety profile, and relatively few drug interactions have been identified. Conclusions Terbinafine is more effective than the gold standard, griseofulvin, in the treatment of tinea pedis and tinea unguinum, with considerably shorter treatment duration in the latter. It has been proven as effective as griseofulvin in the treatment of tinea capitis, tinea corporis, and tinea cruris. Terbinafine does not appear to offer any advantage in the treatment of nondermatophyte infections; its utility in the treatment of systemic infections has yet to be established. Depending on individual institutional costs, terbinafine may be a front-line drug for some superficial infections responding poorly to the current standard of therapy.

Effect of Diet on the Development of Drug Metabolism by Cytochrome P-450 Enzymes in Healthy Infants

Orally administered caffeine and dextromethorphan (DM) were used as pharmacologic probes to determine the effect of infant diet on acquisition of cytochrome P-450 (CYP) enzyme activity during the first 6 mo of life. The caffeine elimination rate constant (ke) was determined from serum, and concentrations of caffeine, DM, and their respective metabolites were measured in urine by high-performance liquid chromatography (HPLC). Caffeine ke was low at 2 wk and displayed a significant positive linear correlation with age (p < 0.001); increasing faster in formula-fed than in breast-fed infants (p < 0.001). This occurred concomitantly with a significant increase in urinary 1,7-dimethylxanthine (17X) and 1-methylxanthine (1X) (p < 0.001), suggesting faster acquisition of CYP1A2 activity in formula-fed infants. The urinary molar ratio of (17X + 1X)/caffeine and age strongly predicted caffeine ke (r2 = 0.65; p < 0.001) irrespective of feeding type. CYP3A4 activity, assessed as the molar ratio of 3-hydroxymorphinan/dextrorphan showed a similar marked increase with postnatal age (p < 0.001) that was also greater in formula-fed than in breast-fed infants. Formula feeding appears to accelerate maturation of caffeine and DM metabolism by increasing the activity of CYP1A2 and CYP3A4, respectively. Dietary modification of CYP activity may modulate drug biotransformation and thus alter systemic exposure to xenobiotics from a very early age.

Concordance between Tramadol and Dextromethorphan Parent/Metabolite Ratios: The Influence of CYP2D6 and Non‐CYP2D6 Pathways on Biotransformation

Cytochrome P4502D6 (CYP2D6) activity has been shown to be a determinant of both the pharmacokinetics and pharmacodynamics of tramadol in adults. This study evaluated the association between CYP2D6 activity, as determined by dextromethorphan (DM) urinary metabolite ratio, and tramadol biotransformation in 13 children (7–16 years). CYP2D6 genotype was determined by XL‐PCR and PCR/RFLP. Phenotype was assessed by HPLC quantitation of DM and its metabolites from a 12‐ to 24‐hour urine collection following a single oral dose of DM. There was only a modest correlation between tramadol/M1 (metabolite 1)plasma concentration or AUC and the DM/dextrorphan (DX) urinary molar ratio in the study cohort; however, when subjects were segregated based on the number of functional CYP2D6 alleles, a much stronger relationship was observed for subjects with two functional alleles, with essentially no relationship evident in those individuals with one functional allele. Further evaluation of these data suggested that the CYP2D6‐mediated metabolite (M1) is formed to a lesser extent, and the formation of the non‐CYP2D6 product (M2) is more pronounced in subjects with one versus two functional alleles. Thus, the number of functional CYP2D6 alleles and the availability of alternative cytochromes P450 capable of metabolizing tramadol may explain the poor association between DM, a well‐characterized CYP2D6 probe, and tramadol in a population of CYP2D6 extensive metabolizers.

Single-dose pharmacokinetics of daptomycin in children with suspected or proved gram-positive infections.

Background: New antimicrobials such as daptomycin fill a void in the growing need for antibiotics effective against resistant Gram-positive pathogens. Although the pharmacokinetics of daptomycin have been well characterized in adults, no studies have evaluated the pharmacokinetics and tolerability in a pediatric population. Methods: Twenty-five children (12–17 years, n = 8; 7–11 years, n = 8; 2–6 years, n = 9) were enrolled in this multicenter, open-label study. Daptomycin was administered as a single 4-mg/kg intravenous dose followed by repeated blood sampling for 24 hours. Daptomycin was quantitated from plasma using a validated high performance liquid chromatography method and pharmacokinetic variables determined using a model-dependent approach. Results: Daptomycin systemic exposure decreased with decreasing age, reflecting more rapid rates of clearance in younger children. Total body exposure estimates in adolescents were approximately 1.7× those observed in children <6 years of age (374.4 versus 215.3 μg*h/L), they were comparable to those observed in adult historic controls. Estimates of apparent elimination half-life averaged 6.7 hours in adolescents, 5.6 hours in children 7–11 years of age, and 5.3 hours in children <6 years of age. One child had an adverse event (infusion site reaction) considered to be related to study drug. Conclusions: Systemic drug exposure after a single weight-adjusted daptomycin dose is reduced in younger children compared with adolescents and adults consequent to an apparent age-associated change in total plasma clearance.