Lisdexamfetamine Dimesylate Effects on the Pharmacokinetics of Cytochrome P450 Substrates in Healthy Adults in an Open-Label,Randomized, Crossover Study

Introduction

This open-label, randomized, two-period drug interaction study assessed lisdexamfetamine dimesylate (LDX) effects on cytochrome P450 (CYP) enzyme (CYP1A2, CYP2D6, CYP2C19, and CYP3A) activity.

Methods

Thirty healthy volunteers were administered the Cooperstown cocktail (CYP1A2 [caffeine 200 mg], CYP2D6 [dextromethorphan 30 mg], CYP2C19 [omeprazole 40 mg], and CYP3A [midazolam 0.025 mg/kg] substrates) or Cooperstown cocktail + oral LDX 70 mg. Blood samples for pharmacokinetic analysis were collected pre-dose and serially for 72 h post-dose. Treatment differences in the primary endpoints, maximum plasma concentration (C_max) and area under the plasma concentration versus time curve from 0 to infinity (AUC_0–∞), were assessed using geometric mean ratios with 90 % CIs.

Results

Geometric least squares (LS) means (without versus with LDX) for C_max (ng/mL) were 5370 versus 5246 for caffeine, 2.43 versus 2.87 for dextromethorphan, 35.23 versus 35.11 for midazolam, and 677.9 versus 466.9 for omeprazole; and for AUC_0–∞ (ng·h/mL) were 56,207 versus 56,688 for caffeine, 34.85 versus 37.27 for dextromethorphan, 92.07 versus 93.04 for midazolam, and 1428 versus 1499 for omeprazole. Geometric LS mean ratios were within the standard bioequivalence testing range, except for omeprazole and dextromethorphan C_max. Parent/metabolite C_max and AUC_0–∞ ratios were similar between treatments except for dextromethorphan/dextrorphan AUC_0–∞ ratio, which was lower with LDX. No serious or severe treatment-emergent adverse events were reported.

Conclusions

LDX did not alter CYP1A2, CYP2D6, or CYP3A activity. A small C_max reduction for omeprazole and its metabolite was observed, possibly reflecting an effect either on the activity of CYP2C19 or omeprazole absorption.

Electronic supplementary material

The online version of this article (doi:10.1007/s40268-015-0090-z) contains supplementary material, which is available to authorized users.     

Effect of CYP2C19*2 and *17 mutations on pharmacodynamics and kinetics of proton pump inhibitors in Caucasians

AIMS

To investigate the impact of CYP2C19 mutations *2-*6 and *17 on acid-inhibition and pharmacokinetics of lansoprazole (L15), omeprazole (O10, O20) and pantoprazole (P40) in Caucasians.

METHODS

CYP2C19 genotyping for *2–*6 and *17 mutations was assessed in subjects who were H. pylori negative in two randomized crossover trials. The influence of CYP2C19 mutations on single and repeated administration of L15 and O10 (study A) and O20 and P40 (study B) was investigated. Pharmacokinetics and the cumulative percentage of time with intragastric pH above 4 (% > pH 4) were assessed on day 1 and 6.

RESULTS

For study A CYP2C19 genotyping found five *1/*1, four *1/*2, one *1/*17 and one *2/*17. For study B the results were six *1/*1, two *1/*2, six *1/*17, one *2/*2 and one *2/*17. For all PPIs AUC was highest in *2/*2 and lowest in *1/*17. On day 1, all PPIs significantly increased percentage >pH 4 compared with baseline. *1/*1 genotype showed no significant acid-inhibition after L15, O10 and O20. *1/*17 genotype showed no significant acid-inhibition after O20 and P40. *1/*2 genotype showed significant acid-inhibition after L15 and O10. On day 6, all four PPIs showed significantly increased acid-inhibition. *1/*1 and *1/*17 showed a significantly increased percentage > pH 4 after treatment with O20 and P40. However, in *1/*1 subjects percentage > pH 4 was not significantly increased after L15 and O10. *1/*2 genotype showed a significant acid-inhibitory effect after repeated dosing with L15 and O10.

CONCLUSIONS

Caucasian subjects with *1/*1 and *1/*17 genotype need stronger acid-suppression therapy, especially during the first days of treatment or with on-demand therapy.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• The influence of CYP2C19 on the kinetics and dynamics of omeprazole, lansoprazole and rabeprazole has been studied in Japanese subjects.
• It has been suggested that subjects with *1/*1 genotype might need stronger acid suppression than *1/*2 and *2/*2 subjects. This suggestion comes from data in Japanese subjects and has not been confirmed in Caucasians.
• Furthermore, a novel CYP2C19 mutation, *17, which mainly occurs in Caucasians has been discovered. This mutation has been associated with clinical failure, but its relevance for therapy with PPIs has not been studied yet.

WHAT THIS STUDY ADDS

• In this study, the influence of CYP2C19 on both the pharmacokinetics and dynamics in Caucasian subjects after single and repeated dosing has been investigated.
• This is the first study showing that Caucasian subjects with *1/*1 and *1/*17 mutations need stronger acid-inhibition. In this study three proton pump inhibitors (omeprazole, lansoprazole and pantoprazole, in different doses) were studied of which pantoprazole had not been studied before in this setting, not even in Japanese.

     

Hydroxylation index of omeprazole in relation to CYP2C19 polymorphism and sex in a healthy Iranian population

Background

Polymorphism of CYP2C19 gene is one of the important factors in pharmacokinetics of CYP2C19 substrates. Omeprazole is a proton pump inhibitor which is mainly metabolized by cytochrome P450 2C19 (CYP2C19). The aim of present study was to assess omeprazole hydroxylation index as a measure of CYP2C19 activity considering new variant allele (CYP2C19*17) in Iranian population and also to see if this activity is sex dependent.

Methods

One hundred and eighty healthy unrelated Iranian individuals attended in this study. Blood samples for genotyping and phenotyping were collected 3 hours after administration of 20 mg omeprazole orally. Genotyping of 2C19 variant alleles *2, *3 and *17 was performed by using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and semi-nested PCR methods. Plasma concentrations of omeprazole and hydroxyomeprazole were determined by high performance liquid chromatography (HPLC) technique and hydxroxylation index (HI) (omeprazole/ hydroxyomeprazole) was calculated.

Results

The CYP2C19*17 was the most common variant allele in the studied population (21.6%). Genotype frequencies of CYP2C19*17*17, *1*17, and *2*17 were 5.5%, 28.8% and 3.3% respectively. The lowest and the highest median omeprazole HI was observed in *17*17 and *2*2 genotypes respectively (0.36 vs. 13.09). The median HI of omeprazole in subjects homozygous for CYP2C19*1 was 2.16-fold higher than individuals homozygous for CYP2C19*17 (P < 0.001) and the median HI of CYP2C19*1*17 genotype was 1.98-fold higher than CYP2C19 *17*17 subjects (P < 0.001). However, subjects with CYP2C19*2*17 (median HI: 1.74) and CYP2C19*1*2 (median HI: 1.98) genotypes and also CYP2C19*1*17 (median HI: 0.71) and CYP2C19*1*1 (mean HI: 0.78) did not show any significantly different enzyme activity. In addition, no statistically significant difference was found between women and men in distribution of CYP2C19 genotypes. Furthermore, the hydroxylation index of Omeprazole was not different between women and men in the studied population.

Conclusion

Our data point out the importance of CYP2C19*2 and CYP2C19*17 variant alleles in metabolism of omeprazole and therefore CYP2C19 activity. Regarding the high frequency of CYP2C19*17 in Iranian population, the importance of this new variant allele in metabolism of CYP2C19 substrates shall be considered.     

Pharmacogenetics of CYP2C19: functional and clinical implications of a new variant CYP2C19*17

AIMS

Cytochrome P450 2C19 metabolizes many important drugs. In 2006, a variant allele (CYP2C19*17) associated with increased activity was discovered, but its likely clinical significance is controversial. Investigators disagree about the phenotype to be assigned to the two CYP2C19*17 genotypes. The aim of this study was to provide a critical summary, helpful to prescribers.

METHODS

We searched MEDLINE for papers on the allele from 2006 and then undertook historical searches through the reference lists of papers retrieved. The relevant information was critically assessed and summarized.

RESULTS

CYP2C19*17 was associated with increased enzymic activity. Substrates studied were omeprazole, pantoprazole, escitalopram, sertraline, voriconazole, tamoxifen and clopidogrel. Most studies used pharmacokinetic variables as outcome measure. For clopidogrel, activated by CYP2C19, pharmacodynamic consequences focused on platelet aggregation. While for most pharmacokinetic parameters of the substrates studied the average value was altered, the range of values showed mostly complete overlap for CYP2C19*1/*17 heterozygotes and wild-type homozygotes. Even for CYP2C19*17 homozygotes, the absolute effect was modest compared with the effect of previously identified loss-of-function alleles. In Helicobacter pylori eradication CYP2C19*2 carriage was associated with an altered eradication rate (odds ratio 4.20, 95% confidence interval 1.23, 16.44) relative to the wild-type, but CYP2C19*17 homozygosity was not. Prevalence of the variant allele was typically <5% in Asians and about four times higher in White and African populations.

CONCLUSIONS

Assignment of CYP2C19*17 homozygotes as extensive metabolizers rather than ultrarapid metabolizers is adequate. CYP2C19*17 genotyping is unlikely to have clinical utility except for drugs with very narrow therapeutic indices.     

Pharmacokinetics and tolerability of voriconazole and a combination oral contraceptive co-administered in healthy female subjects

AIM

To assess the two-way pharmacokinetic interaction between voriconazole and Ortho-Novum® 1/35, an oral contraceptive containing norethindrone 1 mg and ethinyl oestradiol 35 μg.

METHODS

In this open-label, three-period, fixed-sequence study, 16 healthy females received voriconazole (400 mg q12 h, day 1; 200 mg q12 h, days 2–4) (period 1), oral contraceptive (q24 h, days 12–32) (period 2), and combination voriconazole (400 mg q12 h, day 57; 200 mg q12 h, days 58–60) and oral contraceptive (q24 h, days 40–60) (period 3).

RESULTS

Voriconazole geometric mean AUC_τ and C_max increased 46% (12 682–18 495 ng h ml⁻¹; 90% confidence interval [CI] 32, 61) and 14% (2485–2840 ng ml⁻¹; 90% CI 3, 27), respectively, when co-administered with oral contraceptive vs. voriconazole alone. Ethinyl oestradiol geometric mean AUC_τ and C_max increased 61% (1031–1657 ng h ml⁻¹; 90% CI 50, 72) and 36% (119–161 ng ml⁻¹; 90% CI 28, 45), respectively, and norethindrone geometric mean AUC_τ and C_max increased 53% (116–177 ng h ml⁻¹; 90% CI 44, 64) and 15% (18–20 ng ml⁻¹; 90% CI 3, 28), respectively, during voriconazole co-administration vs. oral contraceptive alone. Neither ethinyl oestradiol nor norethindrone levels were reduced in subjects following voriconazole co-administration. Adverse events (AEs) were generally mild, occurring less in subjects receiving voriconazole alone (36 events) vs. oral contraceptive alone (88 events) or combination treatment (68 events); four subjects experienced a severe AE.

CONCLUSIONS

Co-administration of voriconazole and oral contraceptive increased systemic exposures of all analytes relative to respective monotherapy. Although generally safe and well tolerated, it is recommended that patients receiving co-administered voriconazole and oral contraceptive be monitored for development of AEs commonly associated with these medications.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Voriconazole, a broad-spectrum antifungal drug, is a substrate and inhibitor of CYP2C19 and CYP3A4 isozymes.
• Ethinyl oestradiol and norethindrone, components of the combination oral contraceptive drug Ortho-Novum® 1/35, also are substrates of cytochrome P450 CYP2C19 and CYP3A4 isozymes.
• Because co-administration of voriconazole and Ortho-Novum® 1/35 could potentially result in pharmacokinetic interactions that increase systemic exposure of one or both drugs to unsafe levels, clinical studies are needed to define better the two-way pharmacokinetic interaction between these drugs.

WHAT THIS STUDY ADDS

• Although co-administered voriconazole and oral contraceptive did result in increased systemic exposures of all three drugs relative to respective monotherapy, co-administered treatment was generally safe and well tolerated.
• It is recommended, however, that patients receiving co-administered voriconazole and oral contraceptives be monitored for the development of adverse events commonly associated with these medications.

     

Effect of glycyrrhizin on CYP2C19 and CYP3A4 activity in healthy volunteers with different CYP2C19 genotypes

1. The objective of this study was to investigate the interaction between glycyrrhizin and omeprazole and observe the effects of glycyrrhizin on CYP2C19 and CYP3A4 activities in healthy Chinese male volunteers with different CYP2C19 genotypes.

2. Eighteen healthy subjects (six CYP2C19*1/*1, five CYP2C19*1/*2, one CYP2C19*1/*3, five CYP2C19*2/*2 and one CYP2C19*2/*3) were enrolled in a two-phase randomized crossover trial. In each phase, all subjects received placebo or glycyrrhizin salt tablet 150?mg twice daily for 14 consecutive days. The pharmacokinetics of omeprazole (20?mg orally on day 15) was determined for up to 12?h following administration by high-performance liquid chromatography.

3. After 14-day treatment of glycyrrhizin, plasma omeprazole significantly decreased, and those of omeprazole sulfone significantly increased. However, plasma concenetrations of 5-hydroxyomeprazole did not significantly change. The ratio of AUC_0–∞ of omeprazole to omeprazole sulfone decreased by 43.93% ± 13.56% (p?=?0.009) in CYP2C19*1/*1, 44.85% ± 14.84% (p?=?0.002) in CYP2C19*1/*2 or *3 and 36.16% ± 7.52% (p?<?0.001) in CYP2C19*2/*2 or *3 while those of omeprazole to 5-hydroxyomeprazole did not change significantly in all three genotypes. No significant differences in glycyrrhizin response were found among CYP2C19 genotypes.

4. Glycyrrhizin induces CYP3A4-catalyzed sulfoxidation of omeprazole and leads to decreased omeprazole plasma concentrations, but has no significant impact on CYP2C19-dependent hydroxylation of omeprazole.

     

Effect of CYP2C19 polymorphism on nelfinavir to M8 biotransformation in HIV patients

Aims

To evaluate the effect of CYP2C19 polymorphism on nelfinavir and M8 pharmacokinetic variability in human immunodeficiency virus-infected patients and to study the link between pharmacokinetic exposure and short-term efficacy and toxicity.

Methods

Nelfinavir (n = 120) and M8 (n = 119) concentrations were measured in 34 protease inhibitor-naïve patients. Two weeks after initiating the treatment, blood samples were taken before, 1, 3 and 6 h after drug administration. Genotyping for CYP3A4, 3A5, 2C19 and MDR1 was performed. A population pharmacokinetic model was developed to describe nelfinavir-M8 concentration time-courses and to estimate interpatient variability. The influence of individual characteristics and genotypes were tested using a likelihood ratio test. Estimated mean (C_mean), maximal (C_max) and trough (C_trough) nelfinavir and M8 concentrations were correlated to short-term virological efficacy and tolerance using Spearman nonparametric correlation tests.

Results

A one-compartment model with first-order absorption, elimination and metabolism to M8 best described nelfinavir data. M8 was modelled by an additional compartment. Mean pharmacokinetic estimates and the corresponding intersubject variabilities were: absorption rate 0.17 h⁻¹ (99%), absorption lag time 0.82 h, apparent nelfinavir total clearance 52 l h⁻¹ (49%), apparent nelfinavir volume of distribution 191 l, M8 elimination rate constant 1.76 h⁻¹ and nelfinavir to M8 0.39 h⁻¹ (59%) in *1/*1 patients and 0.20 h⁻¹ in *1/*2 or *2/*2 patients for CYP2C19*2. Nelfinavir C_mean was positively correlated to glycaemia and triglyceride increases (P = 0.02 and P = 0.04, respectively).

Conclusions

The rate of metabolism of nelfinavir to M8 was reduced by 50% in patients with *1/*2 or *2/*2 genotype for CYP2C19 compared with those with *1/*1 genotype.

What is already known about this subject

• Nelfinavir is an HIV protease inhibitor, substrate of the transporter P-glycoprotein and metabolized via CYP2C19, CYP3A4 and CYP3A5 enzymes.
• Pharmacokinetic studies have shown wide interindividual variability of nelfinavir concentrations, some of this variability perhaps caused by variant drug metabolism or transporter genes.
• For CYP3A4*1B and CYP3A5*3 polymorphism, results from three studies are in agreement, showing no difference in nelfinavir concentrations between patients with these different genotypes.
• However, for MDR1 and CYP2C19 polymorphism, there have been contradictory studies, showing either no impact on nelfinavir concentration or modified concentrations which could influence virological response.

What this study adds

• Patients with an *1/*2 or *2/*2 genotype for CYP2C19 had a nelfinavir to M8 biotransformation divided by 2 compared with *1/*1 patients.
• No evidence of any influence of MDR1 polymorphism on nelfinavir absorption could be detected.

     

Time-dependent inhibition of human drug metabolizing cytochromes P450 by tricyclic antidepressants

AIMS

To investigate time-dependent inhibition (TDI) of human drug metabolizing CYP enzymes by tricyclic antidepressants (TCAs).

METHODS

CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A/CYP3A4 activities were investigated following co- and preincubation with TCAs using human liver microsomes (HLM) and human recombinant CYP proteins (expressed in Escherichia coli) as the enzyme sources. A two-step incubation method was employed to examine the in vitro mechanism-based inactivation (MBI) criteria. Potential metabolite–intermediate complex (MIC) formation was studied by spectral analysis.

RESULTS

TCAs generally exhibited significant TDI of recombinant CYP1A2, CYP2C19 and CYP2D6 (>10% positive inhibition differences between co- and preincubation conditions). TDI of recombinant CYP2C9 was minor (<10%), and was minor or absent in experiments utilizing recombinant CYP3A4 or HLM as the enzyme sources. Where observed, TDI of recombinant CYP occurred via alkylamine MIC formation, but evidence to support similar behaviour in HLM was limited. Indeed, only secondary amine TCAs reduced the apparent P450 content of HLM (3–6%) consistent with complexation. As a representative TCA, nortriptyline fulfilled the in vitro MBI criteria using recombinant CYP2C19 and CYP3A4 (K_I and k_inact values of 4 µm and 0.19 min⁻¹, and 70 µm and 0.06 min⁻¹), but not with the human liver microsomal enzymes.

CONCLUSIONS

TCAs appear to have minimal potential for MBI of human liver microsomal CYP enzymes involved in drug metabolism. HLM and recombinant CYP (expressed in E. coli) are not equivalent enzyme sources for evaluating the TDI associated with some drugs.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Much of the literature evidence for mechanism-based inactivation (MBI) of CYP by tricyclic antidepressants is limited to studies in rat liver microsomes.
• One report from this laboratory characterized MBI of human recombinant CYP2C8 by nortriptyline.

WHAT THIS STUDY ADDS

• Tricyclic antidepressants form alkylamine metabolite-intermediate complexes with human recombinant CYP enzymes (expressed in Escherichia coli) relatively easily, resulting in time-dependent inhibition.
• Evidence to support similar irreversible inhibition using human liver microsomal (HLM) fractions is limited.
• HLM and recombinant CYP (expressed in E. coli) are not equivalent enzyme sources for evaluating the time-dependent inhibition of human drug metabolizing CYP that is associated with some drugs.

     

Effects of rifampicin on the pharmacokinetics of roflumilast and roflumilast N-oxide in healthy subjects

AIMS

To evaluate the effect of co-administration of rifampicin, an inducer of cytochrome P450 (CYP)3A4, on the pharmacokinetics of roflumilast and roflumilast N-oxide. Roflumilast is an oral, once-daily phosphodiesterase 4 (PDE4) inhibitor, being developed for the treatment of chronic obstructive pulmonary disease. Roflumilast is metabolized by CYP3A4 and CYP1A2, with further involvement of CYP2C19 and extrahepatic CYP1A1. In vivo, roflumilast N-oxide contributes >90% to the total PDE4 inhibitory activity.

METHODS

Sixteen healthy male subjects were enrolled in an open-label, three-period, fixed-sequence study. They received a single oral dose of roflumilast 500 µg on days 1 and 12 and repeated oral doses of rifampicin 600 mg once daily on days 5–15. Plasma concentrations of roflumilast and roflumilast N-oxide were measured for up to 96 h. Test/Reference ratios and 90% confidence intervals (CIs) of geometric means for AUC and C_max of roflumilast and roflumilast N-oxide and for oral apparent clearance (CL/F) of roflumilast were estimated.

RESULTS

During the steady-state of rifampicin, the AUC_0–∞ of roflumilast decreased by 80% (point estimate 0.21; 90% CI 0.16, 0.27); C_max by 68% (0.32; CI 0.26, 0.39); for roflumilast N-oxide, the AUC_0–∞ decreased by 56% (0.44; CI 0.36, 0.55); C_max increased by 30% (1.30; 1.15, 1.48); total PDE4 inhibitory activity decreased by 58% (0.42; 0.38, 0.48).

CONCLUSIONS

Co-administration of rifampicin and roflumilast led to a reduction in total PDE4 inhibitory activity of roflumilast by about 58%. The use of potent cytochrome P450 inducers may reduce the therapeutic effect of roflumilast.