Pharmacogenetics and Drug Exposure

The same dose produces different blood levels and effects in different people, because of genes for drug-metabolising enzymes, body size, sex, co-medications and route of delivery. The evidence here comes from two African efavirenz studies, a Canadian case-control study of gabapentin with opioids, and a small asthma trial of an inhaled drug.

Students often assume dose equals exposure and that interactions come mainly from enzyme-inducing drugs. These studies show genotype can outweigh a famous interaction, that pharmacodynamic combinations can be lethal, and that delivery route can separate benefit from side effects.

Claim ledger

What the evidence shows

Drawn from 4 studies in this library. Mix labels say which citation roles are present; they are not a strength score. Supports means evidence for a finding; Challenges means evidence against a stated position; Qualifies marks scope.

• ○ Limited citations

  Genes can change exposure more than tenfold at the same dose.

  CYP2B6 genotype is a major determinant of efavirenz exposure: in 185 Zimbabwean adults, CYP2B6*6, *18, body weight and sex explained up to 55% of between-person variability in clearance, which fell from 7.01 L/h in extensive to 0.539 L/h in poor metabolisers; carriers of two or more variant alleles had about fourfold higher concentrations.

  1 study
  1. 1Why do people on the same HIV drug dose reach different blood levels?

• ○ Limited citations

  Exposure links genotype to side effects, imperfectly.

  Higher efavirenz exposure tracked neuropsychiatric symptoms in a Ugandan cohort of 197 adults: 74% developed a symptom within 12 weeks, symptomatic patients had higher plasma levels, and CYP2B6 genotype predicted levels at every time point, though the direct genotype-symptom link was only a trend.

  1 supporting · 1 qualifying

  Supports

  1. 1Why do some HIV patients get side effects from efavirenz?

  Qualifies

  1. 1Why do people on the same HIV drug dose reach different blood levels?— Cross-sectional Zimbabwean data found no difference in average levels between patients with and without CNS effects.

  Study comparison

  Study	Role	Design	N	Population	Outcome
  Why do some HIV patients get side effects from efavirenz?2013	Supports	CohortProspective cohort: treatment-naive HIV patients started efavirenz 600 mg daily (plus zidovudine and lamivudine); TB co-infected patients also took rifampicin-based TB therapy. Mid-dose efavirenz levels were measured from day 3 to week 12, five drug-handling genes were genotyped, and neuropsychiatric symptoms were assessed at baseline, week 2 and week 12.	N=197 · 197 patients: 59 with HIV only on efavirenz alone and 138 with HIV-TB co-infection also receiving rifampicin; 89.9% were assessed at week 12.	Newly diagnosed, antiretroviral-naive adults with HIV, with or without tuberculosis, at two national referral hospitals in Kampala, Uganda (2008-2009).	Incidence and type of neuropsychiatric symptoms (sleep disorders, hallucinations, cognition on an adjusted MMSE) over 12 weeks, and their relation to plasma efavirenz concentration, rifampicin co-treatment and genotype.
  Why do people on the same HIV drug dose reach different blood levels?2015	QualifiesCross-sectional Zimbabwean data found no difference in average levels between patients with and without CNS effects.	Cross-sectionalSingle-timepoint plasma efavirenz measurement (12-15 h post-dose) with TaqMan genotyping, analysed by nonlinear mixed-effects population PK modelling in NONMEM plus Monte Carlo simulations	N=185 · 185 patients analysed: 95 recruited on efavirenz-based ART alone and 90 with HIV/TB co-infection also receiving rifampicin-containing TB therapy (60 men, 125 women)	Adults with HIV, some co-infected with tuberculosis, attending two hospitals in Zimbabwe while taking efavirenz-based antiretroviral therapy	Apparent oral clearance of efavirenz and plasma concentration; secondary outcomes were reported central nervous system adverse effects

• ○ Limited citations

  Additive respiratory depression is a real-world, dose-related hazard.

  Combining sedating drugs raises risk: in an Ontario nested case-control study, gabapentin co-prescription with opioids was linked to 49% higher odds of opioid-related death (adjusted OR 1.49), rising to 1.83 at very high gabapentin doses, while NSAID co-prescription showed no link.

  1 study
  1. 1Does taking gabapentin with opioids raise overdose death risk?

• ○ Limited citations

  Local delivery kept systemic exposure, and its side effects, low.

  Route of delivery can separate effect from toxicity: in a crossover RCT of 24 adults with mild allergic asthma, inhaled PDE4 inhibitor GSK256066 cut the early allergen response by 40.9% and the late response by 26.2% versus placebo, with blood levels mostly undetectable and none of the nausea typical of oral PDE4 inhibitors.

  1 study
  1. 1Does an inhaled PDE4 blocker dampen allergic asthma attacks?

Debates

Tensions and limits

Some items are genuine disagreements on the same question. Others mark different assays, populations, or outcomes.

Timeline

How understanding moved

Study years are when the paper was published. Evidence edits are dated changes to this page's claims. Explanations are when PaperFren added a Discovery — not a claim that the science happened that day.

Papers

4 studies in this library bear on Pharmacogenetics and Drug Exposure, ordered by citations.

• Does taking gabapentin with opioids raise overdose death risk?

  People on prescription opioids who were also given gabapentin had about 50% higher odds of dying from an opioid overdose, with the greatest risk at moderate-to-high gabapentin doses.

  PLoS medicine · 2017 · 400 citations

• Why do some HIV patients get side effects from efavirenz?

  Most Ugandan patients starting the HIV drug efavirenz had neuropsychiatric side effects such as vivid dreams, and these were linked to higher blood levels of the drug, which in turn depended on a patient's CYP2B6 gene variant, while taking TB drugs at the same time made no difference.

  BMC infectious diseases · 2013 · 77 citations

• Does an inhaled PDE4 blocker dampen allergic asthma attacks?

  A week of an inhaled PDE4 inhibitor substantially reduced the drop in lung function that people with allergic asthma had after breathing in an allergen, while barely reaching the bloodstream.

  Respiratory research · 2010 · 67 citations

• Why do people on the same HIV drug dose reach different blood levels?

  Two variants of the liver enzyme gene CYP2B6, along with body weight and sex, together explained about 55% of the person-to-person variation in how quickly patients cleared efavirenz.

  BMC pharmacology & toxicology · 2015 · 60 citations

Questions

What is still open

1. Whether efavirenz levels explain CNS side effects differs between studies: the Ugandan prospective cohort linked higher levels to symptoms, while the Zimbabwean cross-sectional study of patients already on therapy found no difference. Timing matters, as Ugandan symptoms arose mostly in the first two weeks.

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