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This study quantified the impact of multiple doses of efavirenz on CYP3A activity via midazolam metabolism using a population pharmacokinetic approach. Healthy volunteers received 1\u2009mg midazolam orally in two sessions: first with a single 600\u2009mg efavirenz dose and then after chronic efavirenz dosing (600\u2009mg\/day for 17\u2009days). Midazolam and 1\u2032\u2010hydroxymidazolam were quantified via LC\u2013MS\/MS, and CYP2B6, CYP3A4, and CYP3A5 genotypes were assessed using TaqMan assays. Seventy\u2010two volunteers (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u200972) completed sampling after the initial dose, and 58 completed both occasions. Non\u2010linear mixed effects modeling was performed using the stochastic approximation expectation maximization estimation method in NONMEM. The base pharmacokinetic model employed was a two\u2010compartment model with first\u2010order absorption and first\u2010order elimination, incorporating proportional error terms for midazolam and 1\u2032\u2010hydroxymidazolam. Covariate analysis utilized a full model approach to assess the impact of CYP3A4 and CYP3A5 genotypes, self\u2010reported sex, and multiple doses of efavirenz as covariates affecting the formation clearance of 1\u2010OH midazolam. CYP3A5 expressors exhibited a 1.27\u2010fold increase in midazolam clearance compared to non\u2010expressors, while CYP3A4 intermediate metabolizers showed a 0.94\u2010fold decrease relative to normal metabolizers. Clearance was also 1.30\u2010fold higher in females compared to males. Multiple doses of efavirenz increased midazolam clearance by 1.92\u2010fold (95% CI 1.65\u20132.28) after accounting for inter\u2010individual variability caused by other covariates. Furthermore,\n                    <jats:italic>K<\/jats:italic>\n                    <jats:sub>a<\/jats:sub>\n                    and bioavailability (\n                    <jats:italic>F<\/jats:italic>\n                    ) increased with repeated efavirenz exposure. In conclusion, this population pharmacokinetic analysis effectively quantified the specific induction effect of multiple doses of efavirenz on CYP3A compared to a single dose of efavirenz.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>Trial Registration:<\/jats:bold>\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"https:\/\/clinicaltrials.gov\/ct2\/show\/NCT00668395\">ClinicalTrials.gov<\/jats:ext-link>\n                    identifier: NCT00668395\n                  <\/jats:p>","DOI":"10.1002\/psp4.70116","type":"journal-article","created":{"date-parts":[[2025,9,24]],"date-time":"2025-09-24T18:41:52Z","timestamp":1758739312000},"page":"2095-2106","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["A Population Pharmacokinetic Approach to Understand the Effect of Efavirenz on\n                    <scp>CYP3A<\/scp>\n                    Activity in Healthy Volunteers Using Midazolam as a Probe"],"prefix":"10.1002","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4978-4593","authenticated-orcid":false,"given":"Kimberly S.","family":"Collins","sequence":"first","affiliation":[{"name":"Division of Clinical Pharmacology, Department of Medicine Indiana University School of Medicine  Indianapolis Indiana USA"},{"name":"Quantitative Medicine Critical Path Institute  Tucson Arizona USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2082-6454","authenticated-orcid":false,"given":"Blessed W.","family":"Aruldhas","sequence":"additional","affiliation":[{"name":"Division of Clinical Pharmacology, Department of Medicine Indiana University School of Medicine  Indianapolis Indiana USA"},{"name":"Department of Pharmacology and Clinical Pharmacology Christian Medical College  Vellore India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0096-3953","authenticated-orcid":false,"given":"Ingrid F.","family":"Metzger","sequence":"additional","affiliation":[{"name":"Division of Clinical Pharmacology, Department of Medicine Indiana University School of Medicine  Indianapolis Indiana USA"},{"name":"Department of Pharmacy, Faculty of Health Sciences Universidade de Bras\u00edlia  Bras\u00edlia Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jessica B. L.","family":"Lu","sequence":"additional","affiliation":[{"name":"Division of Clinical Pharmacology, Department of Medicine Indiana University School of Medicine  Indianapolis Indiana USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8150-3782","authenticated-orcid":false,"given":"Michael A.","family":"Heathman","sequence":"additional","affiliation":[{"name":"Division of Clinical Pharmacology, Department of Medicine Indiana University School of Medicine  Indianapolis Indiana USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6554-0695","authenticated-orcid":false,"given":"Sara K.","family":"Quinney","sequence":"additional","affiliation":[{"name":"Division of Clinical Pharmacology, Department of Medicine Indiana University School of Medicine  Indianapolis Indiana USA"},{"name":"Department of Obstetrics and Gynecology Indiana University School of Medicine  Indianapolis Indiana USA"},{"name":"Center for Computational Biology and Bioinformatics Indiana University School of Medicine  Indianapolis Indiana USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-1513-1295","authenticated-orcid":false,"given":"Zeruesenay","family":"Desta","sequence":"additional","affiliation":[{"name":"Division of Clinical Pharmacology, Department of Medicine Indiana University School of Medicine  Indianapolis Indiana USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,9,24]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa031772"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199912163412501"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1177\/2325957416629561"},{"key":"e_1_2_8_5_1","unstructured":"WHO \u201cConsolidated Guidelines on HIV Prevention Testing Treatment Service Delivery and Monitoring: Recommendations for a Public Health Approach \u201d WHO Team (2022) https:\/\/www.who.int\/publications\/i\/item\/9789240031593."},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1097\/QAD.0000000000001845"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.3390\/biom13010088"},{"key":"e_1_2_8_8_1","volume-title":"Sustiva (efavirenz) Package Insert","author":"BMS","year":"2017"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.105.098160"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/clpt.2012.34"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2013.04.002"},{"key":"e_1_2_8_12_1","unstructured":"Division of Clinical Pharmacology \u201cThe Flockhart Cytochrome P450 Drug\u2010Drug Interaction Table \u201d accessed August 24 2023 https:\/\/medicine.iu.edu\/internal\u2010medicine\/specialties\/clinical\u2010pharmacology\/drug\u2010interaction\u2010flockhart\u2010table."},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.103.049601"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.109.031393"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.109.027706"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00883-10"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01120-08"},{"issue":"1","key":"e_1_2_8_18_1","first-page":"S80","article-title":"CYP2B6 Genetic Variation and Efavirenz Autoinduction Influences CYP2B6 Activity and Efavirenz Exposure in Healthy Volunteers","volume":"93","author":"Metzger I. 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