Drug Interactions Between Voriconazole and Atazanavir Coadministered as Atazanavir/Ritonavir in Healthy Participants: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Drug Interactions Between Voriconazole and Atazanavir Coadministered as Atazanavir/Ritonavir in Healthy Participants (NCT00833482), a non-randomized phase 1 study. The primary outcome is Maximum Observed Plasma Concentration (Cmax) and Minimum Observed Plasma Concentration (Cmin) of Atazanavir, Administered as Atazanavir/Ritonavir With and Without Voriconazole, in Participants Who Are Extensive Metabolizers (EM).

2. Clinical Question

This is a pharmacokinetic question rather than a question about clinical benefit in people with HIV. Although HIV-1 and HIV infections are listed as conditions, the study summary describes healthy participants with functional CYP2C19 alleles. The primary outcome concerns measured plasma concentrations, not symptom improvement, viral outcomes, or comparative effectiveness.

The registry gives the doses and schedules under investigation and identifies the concentration measures. It does not report numerical primary-outcome results, so the magnitude or direction of any concentration change cannot be determined from the registry record. The record also does not report a clinical threshold for interpreting a change in these concentrations.

3. Trial Design

The registry classifies the study as Phase 1, non-randomized, unmasked, and single-group. It records enrollment of 185 and a completed status. The recorded study dates are 2009-09 for the start and 2010-07 for primary completion. The sponsor is Bristol-Myers Squibb.

The study was designed to assess pharmacokinetic interactions in healthy participants with functional CYP2C19 alleles. Its summary describes both directions of interest: the effect of voriconazole, 200 mg BID, on steady-state atazanavir pharmacokinetics when atazanavir is administered with ritonavir, 300/100 mg QD; and the effect of atazanavir/ritonavir, 300/100 mg QD, on voriconazole pharmacokinetics. Listed regimen groups also include voriconazole, 50 mg BID, in groups labelled PM.

Because allocation was non-randomized and masking was absent, the regimen groups should not be interpreted as randomized treatment arms. The registry specifically notes that the arms are not a like-for-like control comparison. The record does not describe the sequence or timing of regimen assignment beyond the primary outcome timeframe, or explain how participants moved between the listed regimens. Those details are not reported in the registry record.

The primary outcome is the maximum and minimum observed plasma concentration of atazanavir, administered as atazanavir/ritonavir with and without voriconazole, in EM participants. Secondary outcomes include ritonavir concentration measures in EM participants and safety outcomes, including adverse events and laboratory, electrocardiogram, and vital-sign abnormalities. The registry lists 14 outcome measures, but the number of listed measures does not indicate how many yielded analyzable results.

The record does not describe a randomized control group, masking procedures, or a statistical analysis plan. It also does not report the rationale for the enrollment target. These omissions limit what can be inferred about how the study was planned and how comparisons were intended to be interpreted.

4. Participant Flow and Accounting

The registry reports how participants moved through each stage of the study. All counts below are exactly as posted; missing counts are not inferred from other stages.

Before assignment: A total of 185 participants were enrolled in the study, and 153 were not treated, because they no longer met study criteria, withdrew consent, or were alternate participants who were no longer needed. The remaining 32 participants received treatment.

Days 1-3

Days 11-20

Reasons for not completing this period:

Days 21-30

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: All participants who were healthy, who had functional CYP2C19 alleles, who received any study drug, and who had concentration-time data available.

5. Baseline Characteristics

The table reproduces the baseline characteristics posted in the registry, which describe the participants analysed at baseline and help show whether the randomized groups were comparable.

6. Primary Endpoint

The registry lists the primary outcome as Maximum Observed Plasma Concentration (Cmax) and Minimum Observed Plasma Concentration (Cmin) of Atazanavir, Administered as Atazanavir/Ritonavir With and Without Voriconazole, in Participants Who Are Extensive Metabolizers (EM), measured over Predose and at 1, 2, 3, 4, 5, 7, 9,13, and 24 hours postdose on Days 20 and 30 of a 30-day cycle.

The primary endpoint concerns the maximum observed plasma concentration (Cmax) and minimum observed plasma concentration (Cmin) of atazanavir, given as atazanavir/ritonavir, with and without voriconazole in EM participants. Concentrations were scheduled for measurement predose and at 1, 2, 3, 4, 5, 7, 9,13, and 24 hours postdose on Days 20 and 30 of a 30-day cycle. The endpoint is reported as a geometric mean with geometric coefficient of variation, in ng/mL.

As general statistical context, Cmax describes the highest concentration observed among scheduled measurements, while Cmin describes the lowest observed concentration. These measures can characterize different parts of a concentration-time profile and can help assess whether coadministration is associated with a change in drug exposure. They are not themselves clinical outcomes.

A geometric mean summarizes measurements on a multiplicative scale and is often useful for concentration data that vary proportionally. The geometric coefficient of variation describes relative variability around that summary. These are general interpretations of the measures; the registry record does not describe the exact statistical calculations or any model used.

The record identifies the endpoint and sampling schedule but does not report the resulting geometric means, variability estimates, or a comparison between regimens. Therefore, the endpoint’s numerical findings and their precision are not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The outcome measures are pharmacokinetic summaries. The primary outcome focuses on Cmax and Cmin for atazanavir in EM participants. Cmax is the highest observed plasma concentration within the scheduled sampling profile, and Cmin is the lowest observed concentration within that profile. These measures describe concentration levels at the sampled times; they are not direct measures of clinical benefit. The registry lists predose and postdose sampling on Days 20 and 30 of a 30-day cycle.

What does a geometric mean describe?

As general statistical context, an arithmetic mean summarizes values by adding them and dividing by their number. A geometric mean instead summarizes values on a multiplicative scale. This can be useful for pharmacokinetic concentrations, where proportional differences may be more relevant than equal absolute differences. A geometric mean is not the same as a median, and it should be interpreted in the context of the scale and calculation used.

The registry identifies the primary endpoint summary as a geometric mean with geometric coefficient of variation. It does not state the specific estimation procedure, any transformation, or whether values were adjusted for other variables. Those methodological details are not reported in the registry record. The label alone does not establish which statistical model or inferential test was used.

What does the geometric coefficient of variation add?

As general explanation, a coefficient of variation expresses variability relative to the scale of the data rather than in the original measurement units. A geometric coefficient of variation is used with geometric summaries to describe proportional spread. It can help readers understand how much individual concentration values vary around a geometric mean. The registry does not give the coefficient values for the primary outcome, so the amount of variability cannot be assessed.

Why do sampling times matter?

Cmax and Cmin depend on the concentration-time observations available. A measured maximum is the highest value among the scheduled observations; it is not necessarily an estimate of a concentration peak occurring between measurements. Likewise, a measured minimum depends on the sampling window and schedule. This is general measurement context, not a claim that the study missed a peak or trough. The registry specifies the sampling times but does not report the observed profiles or discuss how measurements between scheduled times were handled.

Steady-state pharmacokinetics refers generally to concentrations after repeated dosing has reached a stable pattern over time. The study summary says that voriconazole’s effect on steady-state atazanavir pharmacokinetics was assessed. The registry does not provide further details on how steady state was defined or confirmed, so no additional assumption about that procedure is warranted.

How should comparisons be understood?

The study is described as non-randomized, unmasked, and single-group. The primary question compares atazanavir/ritonavir administration with and without voriconazole, but the registry cautions that the arms are not a like-for-like control comparison. As general statistical context, random allocation can help balance measured and unmeasured characteristics between comparison groups. Without randomization, a difference between groups may have explanations other than the regimen contrast. The record does not report methods for adjustment or control of such differences.

Masking is listed as none. In general, masking can reduce the influence of knowledge about assigned treatment on some assessments or decisions. For plasma concentration measurements, the extent to which masking would matter depends on study procedures, which are not described. No claim about actual bias can be made from the absence of masking alone.

What can the analysis record establish?

The registry lists 14 outcome measures and 0 analyses. An outcome measure describes what was intended to be assessed; an analysis record would ordinarily provide statistical findings for an outcome. The listed measures include pharmacokinetic measures and safety outcomes. Because numerical primary-outcome analyses are not reported in the registry record, no effect estimate, uncertainty interval, or significance test can be interpreted.

As general statistical context, a confidence interval communicates uncertainty around an estimate under the assumptions of the method used. A p-value, if reported, addresses compatibility of data with a specified null model and does not measure the size or clinical importance of an effect. The registry does not report a primary-outcome confidence interval or p-value. It also does not report the statistical tests, model specification, or treatment of repeated concentration measurements.

What do the planning assumptions mean?

The record describes planning illustrations based on an observed effect, with a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. The illustrations are planning calculations, not observed power. The effect to detect is described as a stated fraction of the observed effect. Such assumptions can illustrate how a hypothetical future study might be planned, but they do not substitute for the trial’s own design rationale. That rationale is not reported in the registry record.

As general context, over-dispersion occurs when variability is greater than a model assumes; if ignored, uncertainty estimates can be too small. The registry does not report whether over-dispersion was relevant or whether any model requiring that assessment was used. More broadly, statistical methods should be matched to the data structure and endpoint, but the record does not provide enough analysis detail to assess that matching.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists 14 outcome measures, including the primary atazanavir concentration outcome, ritonavir pharmacokinetic outcomes, and several safety outcomes. It does not report how the investigators prioritized or interpreted multiple outcomes, whether any multiplicity adjustment was planned, or how confirmatory findings were distinguished from exploratory findings. Multiplicity handling is not reported in the registry record.

As general statistical context, assessing many outcomes can increase the chance of obtaining an apparently notable finding by chance if each is tested separately. Adjustments or a prespecified hierarchy are possible approaches, but the record does not state that either was used. Since numerical analyses are not listed, the effect of any multiplicity approach cannot be assessed.

The primary outcome population is described as healthy participants with functional CYP2C19 alleles who received any study drug and had concentration-time data available. This definition identifies a population with usable concentration measurements, but the registry does not report how many participants met that definition or how missing concentration measurements were handled. The missing-data strategy is not reported in the registry record.

Enrollment is recorded as 185, but that figure does not establish the number included in the primary analysis. Participants without usable concentration-time data may not meet the stated primary population definition; the record does not quantify such exclusions or explain their causes. The registry also does not report an intention-to-treat approach, a per-protocol approach, or another analysis-population rule.

The record does not report interim analyses, stopping rules, or the statistical analysis plan. The listed planning assumptions do not establish the trial’s original sample-size rationale, and the record does not state that the planning illustrations were used to design this study.

11. Safety Results

The registry reports serious adverse events as affected participants divided by participants at risk.

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 5% reporting threshold.

Most frequent non-serious adverse event terms

The registry reports serious-adverse-event counts separately by regimen group. For Voriconazole, 200 BID (EM), 0 participants were affected among 24 at risk. For Atazanavir/Ritonavir, 300/100 QD (EM), 0 were affected among 24 at risk. For Atazanavir/Ritonavir, 300/100 QD (PM), 0 were affected among 8 at risk.

For Atazanavir/Ritonavir, 300/100mgQD + Voriconazole, 200mgBID(EM), 0 were affected among 21 at risk. For Voriconazole, 50 mg BID (PM), 0 were affected among 8 at risk. For Atazanazvir/Ritonavir, 300/100 QD + Voriconazole, 50 BID (PM), 0 were affected among 8 at risk. These are the registry’s reported serious-event counts; they do not establish that the regimens have equivalent safety.

The record lists other adverse-event counts of 22, 24, 2, 17, 0, and 3 for the respective groups, with the at-risk counts. These are descriptive counts and should not be treated as randomized comparisons. Death counts are not reported in the registry record, and no serious-event terms are listed. The safety summaries do not provide the primary pharmacokinetic results.

12. What the Result Does, and Does Not, Mean

This record describes a study of pharmacokinetic interactions between voriconazole and atazanavir/ritonavir in healthy participants. Its primary question concerns atazanavir maximum and minimum observed plasma concentrations in EM participants, with and without voriconazole. The record also describes assessment of the effect of atazanavir/ritonavir on voriconazole pharmacokinetics.

The posted information establishes the study classification, regimens, endpoint definition, sampling schedule, and certain safety counts. It does not report numerical findings for the primary pharmacokinetic endpoint. Consequently, it does not establish whether atazanavir concentrations changed, how large any change was, or how precisely a change was estimated. Findings for the listed ritonavir outcomes and the reverse-direction voriconazole outcomes are also not reported in the registry record.

This is not a clinical-outcome comparison. The primary endpoint measures drug concentrations, and the study summary describes healthy participants. The record therefore does not answer whether a regimen changes HIV-related outcomes or clinical outcomes in people with HIV. It also does not provide a basis for medical decisions.

The design is non-randomized, unmasked, and single-group, and the registry cautions that the arms are not a like-for-like control comparison. The safety figures are descriptive summaries, not evidence of causal differences between regimens. Zero reported serious adverse events in the listed groups should be read as the registry’s event counts, not as proof that serious events cannot occur or as a basis for comparing safety across groups.

In general, a pharmacokinetic study can characterize concentration patterns that may help inform later research. Its interpretation still depends on the observed estimates, their uncertainty, analysis methods, and the population studied. Numerical endpoint results and important analysis details are not reported in the registry record, so conclusions about the size, precision, or clinical implications of any interaction cannot be drawn from this record alone.

13. Why This Trial Matters Statistically

This study is statistically useful as an example of a question that is narrower than a conventional clinical-outcome comparison. It focuses on pharmacokinetic measures: concentrations of atazanavir and, in secondary outcomes, ritonavir and voriconazole. Such endpoints describe drug exposure rather than changes in health outcomes. Keeping that distinction clear prevents concentration summaries from being read as direct evidence of clinical benefit or harm.

The endpoint definition also illustrates why measurement schedules matter. Cmax and Cmin are derived from concentration observations over time, and the registry specifies a sampling schedule across Days 20 and 30 of a 30-day cycle. The schedule gives context for what the measures represent, although the actual concentration profiles and summary estimates are not reported in the registry record.

The design highlights the importance of distinguishing a regimen contrast from a randomized comparison. Allocation is non-randomized, masking is absent, and the registry warns that the arms are not like-for-like controls. A numerical difference between groups, if available, would need interpretation in light of those design features. Here, primary numerical results are not reported, making the design description more informative than any claim about an effect.

The record also illustrates the difference between an outcome being specified and an analysis result being available. Fourteen outcome measures are listed, while the number of analyses is 0. A detailed endpoint title does not supply an estimate, its uncertainty, or the method used to calculate it. Readers need those elements to judge precision and statistical evidence.

Finally, the safety counts show why descriptive data and comparative inference should be kept separate. Counts can document what the registry reports within regimen groups, but the non-randomized design does not support treating raw group contrasts as causal effects. The study’s statistical value lies in the interaction questions and endpoint structure; the registry record does not include the numerical primary results needed to quantify the findings.

14. Limitations

• The posted summary statistics are the only data these results rest on; patient-level data, full protocols and statistical analysis plans are not available.
• Recalculated results are simple, unadjusted calculations from posted summaries. They do not replace the sponsor's prespecified analysis.

The main limitation for statistical interpretation is that numerical results for the primary endpoint are not reported in the registry record. The record gives no atazanavir Cmax or Cmin estimates, no variability values, and no confidence intervals or tests. The number of analyses listed is 0, so the direction and precision of the primary comparison cannot be assessed.

The study is non-randomized, unmasked, and single-group. The record explicitly cautions that the arms are not a like-for-like control comparison. These features limit causal interpretation of any differences between regimens, including differences in the descriptive safety counts. The record does not explain allocation procedures or report adjustment methods.

The study population is described as healthy participants, with the primary endpoint restricted to EM participants who had concentration-time data available. This differs from a clinical-outcome study in a patient population. The record does not report how many participants contributed to each primary analysis or how missing concentration measurements were handled.

The record gives the endpoint sampling schedule but not observed concentration profiles or details of the statistical model, estimation procedure, or handling of repeated measurements. It does not report a statistical analysis plan, multiplicity approach, interim analyses, or sample-size justification. The PM label appears in regimen groups, but its definition is not reported in the registry record.

These limitations concern what can be learned from the registry record and do not establish that the underlying study lacked methods or results. They mean that the details necessary to evaluate the magnitude, precision, and robustness of the primary findings are not reported in the registry record.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Drug Interactions Between Voriconazole and Atazanavir Coadministered as Atazanavir/Ritonavir in Healthy Participants — NCT00833482.
• Registry record last updated 2012-10-25; status last verified 2012-09.
• Results first posted 2012-10-25.
• Data retrieved from ClinicalTrials.gov on 2026-11-09.
• Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.

18. Record Summary

The record describes a completed Phase 1, non-randomized, unmasked, single-group study with enrollment of 185. It examined pharmacokinetic interactions between voriconazole and atazanavir/ritonavir in healthy participants, including EM and PM-labelled regimen groups.

The primary outcome was atazanavir Cmax and Cmin with and without voriconazole in EM participants, summarized as geometric means with geometric coefficients of variation. The record lists 14 outcome measures and 0 analyses. Numerical primary pharmacokinetic results, the statistical analysis plan, and the study’s sample-size justification are not reported in the registry record.

Serious-adverse-event counts were reported as 0 in each listed regimen group. Other adverse-event counts were also recorded, but group comparisons are descriptive and not randomized. Death counts are not reported in the registry record.