Despite many advances taking place in HIV therapeutics, practicing clinicians struggle with currently available antiretroviral drugs because of incomplete suppression of viral replication, drug toxicities, and the development of drug resistance. The identification of a new class of drugs with a novel mechanism of action, sustained efficacy, favorable pharmacokinetic profile, and acceptable safety record remains a major need of HIV therapeutics.
AMD070 is an investigational drug that belongs to a novel class of antiretroviral drugs, CXCR4 inhibitors, which inhibits X4 strains of HIV from fusion with and entry into CD4 cells by potent, specific, and reversible antagonism of the chemokine receptor, CXCR4.1 The antiviral activity of CXCR4 inhibition has been demonstrated with AMD3100 (a predecessor of AMD070) in vitro, in animal models of HIV infection, and in HIV-infected patients.2-4 The development of AMD3100 as an antiretroviral drug was terminated due to poor oral bioavailability and adverse effects. Though it is structurally unrelated, AMD070 has similar antiretroviral activity in vitro when compared to AMD3100, with EC50 values of 2.3 ng/mL and 1.5 ng/mL, respectively, against HIV-1 NL4.3 in MT-4 cells; the protein-binding-adjusted AMD070 EC90 was 44 ng/mL (assuming 90% protein binding) against HIV-1 in MT-4 cells. In animal studies, the oral bioavailability of AMD070 was calculated to be 20% and 80% in rats and dogs, respectively. Elimination occurred from plasma in a biexponential manner with a rapid initial t1/2 of 1.4 and 0.7 hours in the rat and dog, respectively, and a longer terminal elimination half-life of approximately 10 hours in both species. (Unpublished data on file at AnorMED.)
In the first-in-human phase 1 study of AMD070,5 healthy volunteers tolerated the drug well. AMD070 was well absorbed after oral dosing, with a terminal half-life of 11 to 16 hours. A majority of subjects dosed with a 200-mg, twice-daily regimen attained plasma concentrations at or near in vitro EC90 24 hours after dosing. AMD070 is primarily cleared by metabolism, with <1% of the oral dose appearing unchanged in the urine. In vitro studies using human liver microsomes indicated that it is primarily metabolized by CYP3A4 and that its metabolism likely involves, to a lesser extent, multiple enzymes including CYP2C19, 2A6, 2B6, and 2C8. In a phase 1 drug interaction study conducted in healthy volunteers, ritonavir, an inhibitor of CYP3A4, has been shown to increase the total exposure of AMD070.6 In vitro experiments also showed that AMD070 has a moderate potential for inhibition of CYP2D6 and low potential for inhibition of CYP3A4 and other major isoforms. Its potential for induction seems to be low. (Unpublished data on file at AnorMED.)
Because of the in vitro drug interaction data and the fact that many clinically useful drugs, especially drugs used in the management of HIV infection, are substrates of CYP2D6 and CYP3A4, we performed this clinical study to assess the interactions of steady-state AMD070 with substrates of CYP3A4 (midazolam) and CYP2D6 (dextromethorphan).7 Midazolam is hydroxylated by CYP3A4 and CYP3A5 in vitro, although the CYP3A5 contribution in vivo is unclear and may be limited; the mean half-life in healthy volunteers is 1.9 ± 0.6 hours. Dextromethorphan, primarily a CYP2D6 substrate, has a mean half-life of 7 ± 2 hours, but that ranges from 3 ± 0.5 hours in extensive metabolizers to 30 ± 8 hours in poor metabolizers who carry genotype D6-A and D6-B,8 the mutant alleles associated with a complete lack of enzyme activity.9 Five percent to 10% of Caucasians and 1% to 2% of Asians are known to be poor metabolizers.
Study Design and Population
This was a single-center, open-label, sequential-design drug interaction study designed to compare the pharmacokinetics (PK) of single oral dose midazolam and dextromethorphan in the absence and presence of AMD070 at steady state in healthy subjects. The Johns Hopkins Medicine Institutional Review Board approved the study protocol and informed consent documents. All subjects provided written informed consent before study enrollment.
Healthy men and women age 18 to 55 years with no evidence of medical illness by clinical, EKG, and laboratory evaluation were enrolled in the study. Women with no reproductive potential were eligible. For women with reproductive potential, a negative pregnancy test and agreement to refrain from sexual activity or to practice 2 barrier methods to prevent pregnancy during the study period were required. The use of prescribed and over-the-counter medications, supplements, herbal products, and food and drinks with potential interaction with CYP3A4 or CYP2D6 enzymes were not allowed 2 weeks before and throughout the study period. Subjects with poor-metabolizing or ultra-metabolizing CYP2D6 phenotype were identified using the AmpliChip CYPP450 test (Hoffmann-La Roche, Nutley, NJ) and excluded.
Subjects underwent a screening history, a physical, an EKG, HIV testing, and other laboratory tests to determine study eligibility. Eligible subjects were admitted (day 0) to the inpatient General Clinical Research Center at the Johns Hopkins Hospital for 9 days. An indwelling intravenous catheter was inserted for blood sampling.
The subjects were fasted overnight on every dosing day (from day 1 to day 9, inclusive) and a standard breakfast was served 2 hours after dosing. On day 1 and day 9, the subjects were dosed with a single oral dose of midazolam 5 mg and dextromethorphan 30 mg. AMD070 200 mg was administered twice a day from day 2 to day 9, inclusive.
PK Blood Sampling
Blood samples for midazolam PK analysis were collected at time 0 (predose) and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, and 12 hours postdose. Blood samples for dextromethorphan PK analysis were collected at time 0 (predose) and 0.5, 1, 2, 3, 4, 6, 8, 12 and 24 hours postdose. Blood samples for trough blood concentrations (15 minutes before the morning dose) of AMD070 were collected on days 2, 3, 5, and 7. Blood sampling for AMD070 was performed on day 9 at time 0 (predose) and 0.5, 1, 2, 3, 4, 8, 12, and 24 hours postdose. All blood samples were collected within 5 minutes of prespecified time points, and predose samples were collected within 15 minutes before dosing.
Blood for CD4 and CD8 flow cytometry was also collected predose on days 1, 2, 3, 5, and 7, and both predose and 2 hours postdose on day 9. Additional blood samples were collected on days 10 (day of discharge), 11, 12, and 15 (during outpatient follow-up). Complete blood counts were also measured predose (day 1) and postdose (day 10 and day 15) of AMD070.
A complete history and physical examination was performed during screening, and symptom-directed clinical evaluation was performed at admission, daily throughout the inpatient stay, and anytime clinically indicated. Predose and postdose 12-lead EKG was performed on every dosing day and continuous cardiac monitoring was conducted on day 9. Pregnancy testing was repeated during the hospital stay. Safety laboratory testing (hematology, blood chemistry, liver toxicity and function tests, coagulation panel, and urinalysis) was conducted at predetermined intervals. All adverse events were evaluated and assessed for intensity, relationship to study drug, action taken regarding study drugs, and outcome to date.
All subjects returned to clinic on days 11 and 12 for safety evaluation and to give blood samples for CD4 and CD8 flow cytometry. The final visit was made on day 15 for interim clinical history and symptom-directed physical examination, EKG, and laboratory testing, including a pregnancy test.
All venous blood samples (3 mL) for PK analyses were collected in sodium heparin tubes. They were centrifuged within 30 minutes of collection at 900 g for 10 minutes at 4°C. Plasma from each sample was transferred to 2 cryovials and stored at −20°C until shipment to the analytical sites. All baseline and safety laboratory evaluations and CD4 and CD8 measurement were performed locally at the Johns Hopkins Hospital medical laboratory.
Concentrations of AMD070 in plasma were determined by high-performance liquid chromatography-mass spectrometry using validated methods. Validations included assessment of linearity, within-run and between-run precision and accuracy, selectivity, long-term (frozen), short-term (room temperature), auto-sampler, freeze-thaw, and processed sample stability, extraction efficiency, carryover, the effect of dilution, and assessment of potential over-the-counter and HIV drug interferences. The validated calibration range was from 0.5 to 500 ng/mL for plasma, and was selected based on linearity (R2 > 0.95) and accuracy and precision criteria for the validation runs. The acceptance criteria for accuracy and precision were 15% (20% at the lower limit of quantitation [LLOQ]) deviation and an average ≤15% (≤20% at LLOQ) coefficient of variation (CV). Actual within-run precision and accuracy for the validation runs ranged from 3.7% to 14% (CV) and −11% to 15% deviation. Between-run precision and accuracy ranged from 6.6% to 11% (CV) and −5.2% to 12% (deviation). The maximum validated dilution factor was 100-fold. Sample runs were accepted or rejected based on results obtained for quality control (QC) samples included in each run: at least 67% (eg, 6 out of 9) of the QC samples were required to be within ±15% of their respective nominal values. The coefficient of determination (R2) must be >0.95.
Standard calibrators, QC samples, and study samples were prepared and analyzed in an identical manner. Briefly, samples (100 μL) were heated for 30 minutes at 57°C, followed by addition of 50 nL of a 0.5-mg/mL internal standard solution (AMD11025, a structural analog of AMD070) and 50 μL of a 1-N sodium hydroxide (NaOH) solution. After mixing briefly, 1.0 mL of methyl tert-butyl ether (MTBE) was added, and the samples were vortexed (10 minutes) and then centrifuged (3 minutes, >10,000 rpm). Samples were then frozen at ≤−60°C for approximately 60 minutes. The MTBE layer was decanted into a second tube and evaporated to dryness in a water bath at 30°C under nitrogen. After reconstitution in 200 μL of 5/95/0.1% ACN/Water/TFA, the samples were analyzed by reversed-phase high performance liquid chromatography (RP-HPLC) with MS/MS detection (mobile phase: 7/93/0.1% acetonitrile/water/triflouroacetic acid [TFA], flow rate: 0.5 mL/min, run time: 4.5 min). Detection by MS/MS incorporates an electrospray interface in positive ion mode.
Analysis of Midazolam and Dextromethorphan
Concentrations of dextromethorphan and midazolam in human plasma were determined by liquid chromatography tandem mass spectrometry (LC-MS/MS) using a validated method that permitted determination of both analytes in a single sample. Dextromethorphan and midazolam were extracted from human plasma using liquid-liquid extraction after addition of a deuterated internal standard. The reconstituted extract was analyzed using gradient liquid chromatography coupled with tandem mass spectrometry in positive ionization mode. The validation of this method included assessment of linearity, selectivity, intrarun and interrun precision and accuracy, long-term storage (1, 3, and 6 months) stability, short-term (4 days) stability, room temperature stability (16 hours), in-process (auto-sampler) stability, 3 cycles freeze-thaw stability, extraction efficiency, carryover, the effect of dilution, and matrix effect on ionization. The validated calibration range was from 0.10 to 100 ng/mL for both dextromethorphan and midazolam. The LLOQ for both analytes was determined to be 0.10 ng/mL, based on 5 different QC sample runs. Precision and accuracy criteria were set at CV ≤15% and relative error (RE) ≤15%, respectively (except at the LLOQ, where both were set at ≤20%). Actual intrarun precision and accuracy for the sample analysis runs based on QC samples included in each run ranged from 4.9% to 11.9% (CV) and −2.4% to 2.0% (RE) for dextromethorphan and from 2.7% to 5.2% (CV) and 2.7% to 0.4% (RE) for midazolam.
Concentration-time plots were visually examined for all drugs and PK periods. PK parameters for AMD070, midazolam, and dextromethorphan were calculated via noncompartmental analysis using WinNonlin software (Professional Version 4.1; Pharsight, Mountain View, CA), including maximal plasma concentrations (Cmax), time to reach Cmax (Tmax), area under the concentration time curve (AUC0-τ) from 0 to 12 hours (midazolam, AMD070) or 24 hours (dextromethorphan), terminal elimination rate constant (λZ), terminal elimination half-life (t1/2), total apparent oral clearance (Cl/F), and apparent volume of distribution (V/F). Single-dose PK parameters were calculated for midazolam and dextromethorphan, alone and in the presence of steady-state AMD070. Trough concentrations of AMD070 from days 2, 3, 5, 7, and 9 were evaluated to ascertain whether AMD070 had attained steady state by the PK period on day 9.
Descriptive and statistical analyses were performed using Stata statistical software (Intercooled Stata 9.2; StataCorp, College Station, TX). The mean concentrations and standard deviation of plasma concentrations for all 3 study drugs were calculated. The measure of geometric mean ratio (GMR) and 90% confidence interval (CI) was used to compare the Cmax, Tmax, AUC0-τ and t1/2 of midazolam and dextromethorphan alone and in the presence of AMD070. The achievement of steady state of AMD070 was assessed by examination of the slope from the linear regression of log-transformed trough plasma concentrations and time treated as a continuous variable, and by the analysis of the trough plasma concentrations at the end of a 12-hour dosing interval using analysis of variance.
We calculated the sample size of 12 on the basis of the intraindividual CV of Cmax (which is similar for both midazolam and dextromethorphan) and the GMR of oral midazolam resulted from the metabolic inhibition by St. John's wort10 observed in previous studies. This sample size will provide 80% power (with 5% 2-sided alpha) to detect at least 40% difference in PK parameter estimates comparing the probe drug (dextromethorphan or midazolam) alone and in the presence of the inhibiting drug (AMD070).
Clinical and Laboratory Findings
Twelve healthy subjects enrolled in and completed the study. Nine of 12 subjects were African Americans. Three of the subjects were female. The mean age was 40 years (range 22 to 53 years). All subjects tolerated the study procedures and study drugs well. Mild adverse effects were observed in 8 out of 12 subjects (headache, sinus tachycardia, GI discomfort, dry mouth, nasal congestion) and all resolved spontaneously in <12 hours without medical interventions. One subject with a history of persistent asymptomatic bradycardia developed a transient syncopal episode after smoking tobacco and rapidly rising from sitting. This event lasted a few minutes and resolved without any interventions, and was considered probably not related to the study drugs. There were no clinically significant changes from the baseline laboratory and EKG findings in all other subjects, except significant leukocytosis in all subjects.
The midazolam mean concentration-time plots, when comparing the periods with and without AMD070, showed similar peaks, but with a divergence in concentrations at all times beyond 2 hours after dosing, with greater concentrations in the presence of AMD070 (Fig. 1A). A 33% increase in midazolam AUC (GMR 1.33, 90% CI: 1.15 to 1.61) and a 32% decrease in midazolam Cl/F (GMR 0.72, 90% CI: 0.64 to 0.86) occurred with the addition of AMD070 (Table 1). There were no significant changes in other midazolam PK parameters.
On visual inspection, the dextromethorphan mean concentration-time plots, with and without AMD070, diverged quickly after the dose and continued diverging throughout the observation period, but these differences were highly variable and were not statistically significant (Fig. 1B). In the presence of AMD070, there was a significant 152% and 186% increase in, respectively, the maximal concentrations (GMR 2.52, 90% CI: 1.99 to 4.24) and AUC (GMR 2.86, 90% CI: 2.20 to 5.10) of dextromethorphan (Table 1). We observed similar 50% or more decreases in the V/F (GMR 0.41, 90% CI: 0.35 to 0.59) and Cl/F (GMR 0.37, 90% CI: 0.31 to 0.59) of dextromethorphan, without a statistically significant change in the half-life.
AMD070 reached the steady state by the fifth day of 200-mg, twice-a-day dosing (mean trough concentrations are not statistically different than day 9; Figure 2). AMD070 was absorbed well, reaching a median (interquartile range [IQR]) maximal concentration of 1130 ng/mL (712 to 1638 ng/mL) in 3 hours (2 to 3 hours) with an estimated AUC0-τ of 3282 ng·hr/mL (2327 to 4919 ng·hr/mL) (Fig. 2). AMD070 showed a V/F of 218 L (161 to 412 L), Cl/F of 61 L/hr (41 to 87 L/hr), and half-life of 2.6 hours (2.2 to 3.5 hours). Due to the short 12-hour sampling interval with few postdistribution plasma samples, caution is in order in interpreting the V/F and half-life estimates, both of which are dependent upon terminal elimination, are highly sensitive to dosing interval, and differ from estimates in prior studies with longer observations.
The majority of subjects showed leukocytosis, as expected. There is a median (IQR) 33% (19% to 48%) increase in predose total white blood cell count by the end of the 7-day administration of AMD070 (day 10) compared to baseline (day 1) (P = 0.002, Wilcoxon signed-rank test). There were no statistically significant changes in predose absolute CD4 T cells after 1 week on AMD070 compared to baseline (day 9-day 1 ratio, median [IQR] 0.95 [0.79, 1.03]; P = 0.27, Wilcoxon signed-rank test).
Our data suggest that the steady-state AMD070 concentrations achieved on a 200-mg, twice-daily dosing regimen are associated with a significant increase in plasma drug concentrations of both of our probe drugs, midazolam and dextromethorphan, which are substrates of CYP3A4 and CYP2D6, respectively. The increase in midazolam total drug exposure (AUC) in the presence of AMD070 without changes in the half-life is likely due to an increase in bioavailability, secondary to inhibition of presystemic intestinal and hepatic metabolism, which is also supported by the parallel decrease in both Cl/F and V/F. Orally administered midazolam is predominantly and selectively metabolized by both hepatic and intestinal CYP3A4, and, to a limited extent, CYP3A5.11 In other studies, CYP3A4 inhibitors cause a greater degree of inhibition of oral midazolam metabolism compared to intravenous form,12 and midazolam also has been shown to have an intermediate to high hepatic extraction ratio (mean ratio 0.44, SD 0.14).13 There are a number of pharmacokinetic models indicating perfusion-limited metabolism for such drugs with a large hepatic extraction ratio,14 and clinical evidence suggests that the clearance of midazolam is influenced more by hepatic blood flow than by intrinsic enzymatic activity.15,16
There has also been some in vitro evidence that P-glycoprotein plays a complex role in midazolam disposition, in that P-glycoprotein inhibition results in both enhanced absorption across intestinal CACO-2 cells and increased formation of the 1-OH metabolite of midazolam.17 It is common for substrates of CYP3A4 to also be P-glycoprotein substrates; the regulation of CYP3A4 and P-glycoprotein are also both regulated by the nuclear membrane pregnane × receptor, resulting in common inhibition of both CYP3A4 and P-glycoprotein by drugs like ritonavir.18,19 Accordingly, the bioavailability changes may be partially due to such a P-glycoprotein effect, because AMD070 seems to be a P-glycoprotein substrate in CACO-2 experiments in vitro (unpublished data on file at AnorMED). It may be worthwhile to differentiate the effect of AMD070 on CYP3A4 versus P-glycoprotein, using a P-glycoprotein-specific probe such as digoxin,20-22 which can be administered safely with the midazolam probe.23 Although the magnitude of the midazolam interaction was modest-a 33% increase in AUC and no change in peak concentrations-exploration of AMD070 interactions with other 3A4 substrates likely to be used in HIV care may be useful, especially for drugs with narrow therapeutic index or drugs for which pharmacodynamic effects are relatively more sensitive to total exposure than to peak concentrations.
We observed a large, >2.5-fold increase in Cmax and AUC for our probe drug dextromethorphan in the presence of AMD070. CYP2D6 is responsible for more than 97% of the oral clearance of dextromethorphan.24 CYP2D6 is a polymorphic drug-metabolizing enzyme involved in the metabolism of more than 30 clinically important drugs.25 Although we did not test for any clinical effects, changes of this magnitude in other 2D6 substrates are likely large enough to result in changes in clinical drug response, affecting either efficacy or toxicity. Some drugs metabolized by CYP2D6 (eg, anticonvulsants, beta-adrenergic antagonists, benzodiazepines, and antimalarial drugs) have a relatively narrow therapeutic window. The impact of CYP2D6 inhibition by AMD070 on certain drugs of clinical importance should be evaluated individually.
We excluded poor metabolizers (7% to 10% of the white population and 2% to 7% of the African American population) and ultra-rapid metabolizers (4% to 5% of the general population) to keep the phenotype as uniform as possible in this small study. The degree of changes in PK parameters of dextromethorphan attributed to AMD070 was greater than what was observed in midazolam. As with midazolam, this increase in AUC without a noticeable change in the half-life may be largely explained by a change in bioavailability secondary to an inhibition on presystemic metabolism. The parallel reduction in both Cl/F and V/F for dextromethorphan-similar to what is seen with midazolam, although more than twice the magnitude-is also consistent with an increase in bioavailability. This clinical finding is consistent with the in vitro data (unpublished data on file at AnorMED), where AMD070 showed a moderate potential for inhibition of CYP2D6. As with midazolam, it may be worthwhile to explore whether this inhibition may be hepatic, intestinal, or both, because there has been preclinical26,27 and clinical28 evidence of possible involvement of P-glycoprotein in dextromethorphan disposition.
The finding of leukocytosis in our study is consistent with the first-in-human study of AMD0705 and the clinical studies of another CXCR4 antagonist, AMD3100, in healthy volunteers4 and oncology patients.29 The leukocytosis is believed to result from a drug-induced, dose-dependent mobilization of cells from a wide range of leukocyte lineages, including stem cells, from the bone marrow.30 This potentially results from inhibition of the CXCR4 receptor on leukocyte lineage cells and the interaction with cognate receptors on bone marrow stromal cells. Clinical application of this stem-cell mobilization effect of AMD3100 has been studied in previous clinical studies,31 and further evaluations are in progress.
In conclusion, our study demonstrates that AMD070, a novel HIV CXCR4 antagonist, substantially inhibits dextromethorphan, a probe drug for CYP2D6 metabolism, more than 2.5-fold (Cmax and AUC) and inhibits midazolam, our CYP3A4 probe drug, by a modest 33% (AUC only). The inhibition of these major drug-metabolizing enzymes by AMD070 may result in clinically beneficial or deleterious effects, depending on the interacting drug, and may require dose adjustment for certain substrates of these enzymes. Specific AMD070 interactions with CYP3A4 and, especially, CYP2D6 substrate drugs commonly used in the care of HIV-infected patients, such as antidepressants, antihypertensive drugs (beta blockers), and narcotic analgesics, should be investigated.
The authors wish to thank our healthy volunteers for their participation in this study and the study team members of Drug Development Unit at The Johns Hopkins Hospital.
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Keywords:© 2008 Lippincott Williams & Wilkins, Inc.
AMD070; drug interaction; CYP3A4; CYP2D6; CXCR4 inhibitor